Secondary Logo

Journal Logo

Review

The “mitochondrial stress responses”: the “Dr. Jekyll and Mr. Hyde” of neuronal disorders

Patergnani, Simone1; Morciano, Giampaolo1; Carinci, Marianna1; Leo, Sara1; Pinton, Paolo1,2; Rimessi, Alessandro1,2,*

Author Information
doi: 10.4103/1673-5374.339473
  • Open

Abstract

Introduction

Mitochondria are ubiquitous organelles in eukaryotic cells that play a key role in many different cellular processes that span from adenosine 5′-triphosphate (ATP) synthesis, production of reactive oxygen species (ROS), metabolism of amino acids, regulation of cell death and calcium (Ca2+) homeostasis (Suomalainen and Battersby, 2018; Danese et al., 2021; Patergnani et al., 2021a). They consist of an outer mitochondrial membrane (OMM) and an inner mitochondrial membrane (IMM) that define an intermembrane space and an internal matrix, where the mitochondrial DNA (mtDNA) is located. On the IMM are accommodated the proteins involved in the electron transport chain and ATP production (Pfanner et al., 2019). Among all mitochondrial proteins, 13 of the proteins involved in the oxidative phosphorylation are encoded by mtDNA and the remaining ~1200 by the nuclear genome and imported, in an unfolded state, into the organelle through the translocons of the outer and inner membrane complexes, respectively (Mai et al., 2017). Given the crucial role of mitochondria in regulating several cellular processes, their efficient function is fundamental also in the nervous systems. Hence, it is not surprising that the accumulation of mitochondrial dysfunctionalities plays a key role in the pathogenesis of different diseases, including neuronal disorders (ND) (Han and Xu, 2021). The mitochondrial quality control is operated through the coordination of diverse mitochondrial stress responses, mechanisms that intervene to ensure cell and mitochondrial homeostasis (Patergnani et al., 2020a). In addition, many findings assign to mitochondria an alternative role in triggering and sustaining the cellular inflammatory response to different stimuli, introducing a new concept: the “mito-inflammation”. Despite distinct clinical and pathological hallmarks, the mitochondrial stress responses significantly impact the pathogenesis of ND, resulting in the “Dr. Jekyll and Mr. Hyde” for these diseases: (1) Compensatory mitochondrial hyperfusion: an alteration in mitochondrial dynamics which favors the fusion of mitochondria to perform the functional complementation. (2) Mitophagy: a selective autophagic response that segregates and eliminates dysfunctional mitochondria. (3) Mitochondrial unfolded stress response (UPRmt): a mitochondria-nucleus transcriptional program, triggered by proteotoxic stress, which promotes mitochondrial proteostasis, mitochondrial biogenesis, metabolic adaptations, and ROS detoxification to lead survival and mitochondrial network recovery. (4) Mito-inflammation: the mitochondria-mediated inflammation, that occurs to preserve cell integrity, but when exacerbated, it promotes detrimental effects becoming a cause of pathogenesis of several inflammatory-related diseases. (5) Apoptosis: an irreversibly cellular response activated by drastic and prolonged stress.

Their activation contributes to limiting the expansion of mitochondrial stress providing a protection role (the good represented by Dr. Jekyll); however, dysregulation or abnormal activation may exacerbate the mitochondrial stress leading to deleterious consequences (the evil represented by Mr. Hyde).

In this review, we describe the diverse mechanisms activated by mitochondrial stress and how they are implicated in the development and progression of the most common ND, including Parkinson’s disease (PD) and Alzheimer’s disease (AD).

Search Strategy and Selection Criteria

All years were chosen in the search. These searches were performed between June and December 2021 by using PubMed database.

Mitochondrial Stress Responses in Neuronal Disorders

The molecular and signaling mechanisms by which mitochondria respond to a stress signal begin with basic defense mechanisms (such as the simple antioxidant response resulting from excessive ROS production) and end with highly connected and tuned processes, which permit to maintain the correct functioning of the mitochondrial network and the cell (Table 1). These protective mitochondrial responses often hide a dark side; they may turn into deleterious responses if their activation is abnormal and persists over time. The next sections aim to explore these specialized mechanisms and link their contribution to the pathogenesis of different ND.

T1
Table 1:
Summary of key components of the pathway regulating the mitochondrial stress responses

The Role of Compensatory Mitochondrial Dynamic in Neuronal Disorders

Mitochondria are dynamic interconnected organelles, which constantly undergo cycles of fusion and fission that, together with de novo biogenesis and mitophagy, maintain their physiological integrity and control inter-organellar connections to participate in fundamental cellular processes (Marchi et al., 2014). In general, fission is responsible to generate smaller mitochondria, ensuring an efficient organization and movement within the cell, and permitting to the mitochondrial population to be inherited. Mitochondrial fusion consents to the sharing of material between mitochondria to guarantee a balanced mitochondrial network at both functional and structural levels. Alterations in the mitochondrial re-organization are increasingly associated with the development and progression of ND. This section aims to describe the machinery involved in mitochondrial dynamics and clarify their contribution to ND.

Mitochondrial dynamics

Mitochondria fission and fusion are regulated by a plethora of proteins, the majority belonging to the family of dynamin-related GTPases (Zhang et al., 2019a). The main protein involved in the mitochondrial fission process is the cytosolic GTPase dynamin-related protein-1 (DRP-1). DRP-1 is reversibly associated with OMM after its recruitment by many adaptors [mitochondrial dynamics proteins of 49 and 51 kDa, (MID49 and MID51), mitochondrial fission factor, and mitochondrial fission 1] that mediate the binding (Loson et al., 2013). Upon cellular stimulation, post-translational modifications occur to DRP-1 for its mitochondria recruitment, where it induces scission upon GTP hydrolysis by constriction of OMM (Koirala et al., 2013).

Fusion of mitochondria consists of two steps, where firstly OMM and after IMM of two mitochondria that both express mitofusin (MFN) are fused (Guillery et al., 2008). The activity and amount of MFN are modulated by different post-translational mechanisms, such as de-ubiquitination that stabilizes and activates MFN, or phosphorylation events, which trigger MFN inhibition and degradation (Chen and Dorn, 2013; Yue et al., 2014; Pyakurel et al., 2015). The fusion is also mediated by the 120KDa dynamin-like GTPase protein optic atrophy 1 (OPA1) and it is coordinated by the member of the mitochondrial solute carrier family SLC25 named SLC25A46 (Cipolat et al., 2004; Abrams et al., 2015; Li et al., 2017). In the cells, there are two isoforms of OPA1, depending on its alternative splicing and proteolytic cleavage occurring in mitochondria: long-OPA1 (L-OPA1) and short-OPA1. The balance between them guarantees the physiological mitochondrial morphology. Upon apoptotic stimuli, L-OPA1 is converted to the shortest one to inhibit mitochondrial fusion (Ishihara et al., 2006). The balancing between mitochondrial fusion and fission is fundamental to preserve the overall shape of mitochondria. If it lacks, fragmentation of the mitochondrial network may occur, thereby facilitating the segregation of dysfunctional mitochondria and their consequent elimination by mitophagy or, under abnormal stress conditions, it is responsible for cytochrome c (cyt-c) release and apoptosis (Oettinghaus et al., 2016). During the apoptotic event, the B-cell lymphoma 2 (BCL2) Associated X (BAX) and DRP1 translocate to mitochondria where cooperate to promote the DRP1-mediated fission and inhibit the MFN2-mediated fusion, causing mitochondrial fragmentation. Furthermore, BAX forms channels on the OMM, favoring mitochondrial permeabilization and release of cyt-c. Coincident with BAX activation during apoptosis, the BAX/BAK-triggering DRP1-sumoylation favors the mitochondrial fragmentation stabilizing the association of the fission protein to the mitochondrial membrane (Wasiak et al., 2007). In line with this, the expression of a DRP1 mutant inhibits apoptosis preventing mitochondrial fragmentation (Frank et al., 2001). Simultaneously, modest levels of mitochondrial and endoplasmic reticulum (ER) stress induce an increase in the fusion process, which promotes the formation of long filamentous mitochondria to recover partial functional reductions and thus protect the mitochondria from potential damages. However, whether the stress persists, this compensatory phenotype is lost (Lebeau et al., 2018).

Currently, the phenomenon of compensatory mitochondrial hyperfusion is not totally understood as much evidence matched it either to pathological states (Ueda and Ishihara, 2018; Longo et al., 2020) or with protective transient mechanisms against aging and neurodegeneration (Mitra et al., 2009; Tondera et al., 2009; Lebeau et al., 2018).

Implications of mitochondrial dynamics in neurodegeneration

Overall, mitochondrial fusion is a protective event in neurons, as it allows the exchange of a plethora of factors (mtDNA, lipids, proteins, equal distribution of metabolites), which would mitigate any damage to the mitochondria, maximizing their oxidative capacity and reducing heteroplasmy (Chen et al., 2007). The physiological balance existing between fusion and fission is deeply impaired in ND in favor of a burst of mitochondrial fragmentation, such as in PD (Santos et al., 2015), AD (Wang et al., 2009), Huntington (Song et al., 2011) and Prion disease (Yang et al., 2017). In agreement, the majority of mitochondrial fusion proteins are downregulated (Flippo and Strack, 2017). However, a transitory mitochondrial response aimed to counteract certain types of pathological stressful conditions through the hyperfusion of the mitochondrial network exists. Events in which a compensatory hyperfused state of the mitochondrial network provides pro-survival effects are firstly described in 2009 in cells stressed by a small number (to date) of stressors, including ultraviolet light, serum deprivation, and chronic inhibition of protein synthesis (Tondera et al., 2009). The form of stress-induced compensatory mitochondrial hyperfusion (SIMH) is a transitory state induced by modest levels of damage. A mechanism independent from MFN2, which requires the expression of L-OPA1 and MFN1, is sustained by the IMM stomatin-like protein 2 (Tondera et al., 2009). This allows maintaining an adequate ATP production and gain of function in cell resistance to modest stress.

L-OPA1 is currently considered a critical component of the whole protein expression pattern in neurodegeneration as it ensures, through different molecular pathways, cristae morphology, ATP production, and a correct function of electron transport chain during neuronal stress (Quintana-Cabrera et al., 2021). To ensure L-OPA1 stability is necessary prohibitin (PHB), which acts as a scaffold at the IMM (Kasashima et al., 2008), and a balanced function of the peptidases metalloendopeptidase (OMA1) and ATP-dependent zinc metalloprotease (YME1L), which process the cleavage of OPA1. Consistent with this, following a toxic insult that promotes mitochondrial dysfunction and energy depletion, OMA1 and YME1L result degraded, and their proteolytic processing to OPA1 is lost, thereby affecting the recovery of mitochondrial morphology, which occurs following a stress-induced fragmentation (Rainbolt et al., 2016). The absence of PHB at neuronal levels triggers neurodegeneration in mice caused by Tau proteins aggregation (Korwitz et al., 2016). The consequent stabilization of OPA1 by the loss of OMA1, which decreases the adverse processing of the fusion protein, promotes protection from neuroinflammation and apoptosis (Korwitz et al., 2016). Interestingly, this OPA1 processing mediated by PHB and OMA1 in neurons can be also modulated by the mitochondrial phospholipid cardiolipin (CL). Indeed, it has been recently demonstrated that CL exists in a molecular complex composed of PHB and OMA1, which is fundamental for promoting the OMA1 turnover in neurons (Anderson et al., 2020). In confirmation of the critical role of OPA1 in neurodegeneration, it has been demonstrated that mutations in OPA1 are the main cause for dominant optic atrophy, an inherited disease that affects the optic nerve integrity (Delettre et al., 2000). Syndromic patients harboring dominant optic atrophy suffer from a progressive loss of retinal ganglion cells accompanied by other symptoms, such as deafness, ataxia, and myopathy (Baker et al., 2011). Furthermore, the patients also display markers of dysfunctional mitochondria and a compromised mitochondrial network, thereby suggesting the importance of the fusion mechanism in a neurodegenerative status. Experiments conducted in an OPA1 mouse model carrying the recurrent OPA1delTTAG mutation (present in approximately 30% of all dominant optic atrophy patients) confirmed this possibility. OPA1delTTAG mutation leads to progressive visual failure and loss of locomotor behavior, inducing severe mitochondrial dysfunctions (Sarzi et al., 2012). In skeletal muscle, the OPA1delTTAG mutation-dependent mitochondrial dysfunction was accompanied by an increase in autophagy, mitophagy, and mitochondrial proliferation (Sarzi et al., 2012). This excessive mitochondrial turnover may alter the ultrastructure of mitochondria and provoke myopathy and weakness. Preserving an optimal mitochondrial network is also fundamental for cellular metabolism. Profound metabolic signatures have been unveiled in mice with OPA1delTTAG mutation since they display alterations in the concentrations of phospholipids, amino acids, acylcarnitines, and carnosines (Chao de la Barca et al., 2017). In line with this, OPA1delTTAG mutation also affects the size of axonal mitochondria, which reflects in a downregulation of the (re)myelination status in different central nervous system tracts (Ineichen et al., 2021). Interestingly, this effect was also found in mice with MFN2R94Q mutation (Ineichen et al., 2021), confirming the relevant role of the mitochondrial network for the brain. The neural stem cells activated SIMH to counteract the exposure to nicotine, which in turn induced mitochondrial ROS production, mtDNA damage, and excessive mitophagy. This study indicated that a short-term exposure to nicotine is a stressful condition, sufficient to induce mitochondrial dysfunction and alteration in mitochondrial quality control, contributing to cellular aging (Zahedi et al., 2019). The SIMH seems to have beneficial effects only for short-term adaptions. A chronic induction of SIMH led to further stress caused by a static drop of mitochondrial turnover in the absence of fragmentation and mitophagy, as reported in apolipoprotein E (APOE) expressed astrocytes. Indeed, the severe reduction of MFN1 ubiquitination concurs in maladaptive phenotypes in AD, where APOE constitutes a major risk factor (Schmukler et al., 2020).

The antioxidant activity of glutathione (GSH) is also accompanied by compensatory mitochondrial hyperfusion with the concomitant protection of cells from death and excessive mitophagy (Shutt et al., 2012). Many neurodegenerative disorders are characterized by increased oxidative stress which is widely recognized as a key contributor in the progression of the disease, such as in AD and PD (Chen et al., 2012). In these contexts, a tight feedback loop exists, particularly when a proteostatic stress induces ROS production, which in turn exacerbates the proteostatic damage (Angelova and Abramov, 2018; Wang et al., 2021). In response to increased oxidative stress, neuronal cells use GSH to neutralize ROS during stressful conditions, converting its oxidized form glutathione disulfide. The link between glutathione disulfide accumulation and mitochondrial remodeling relies on the ability of the enzyme to modify several disulphide bonds, especially targeting cysteines (Okumura et al., 2011). MFNs reach in these amino acids and are the main protein targets to add new disulphide bonds, stabilizing them and promoting mitochondrial hyperfusion (Shutt et al., 2012). GSH not only protects cells from ROS, but also from other dangerous compounds, like the highly electrophilic aldehyde 4-hydroxy-trans 2-nonenal (4-HNE), an end-product of lipid peroxidation. In this case, the enzyme glutathione S-transferases (GSTs) mediates the conjugation of 4-HNE to GSH as a substrate (Alin et al., 1985). It has been demonstrated that 4-HNE represents a cause of oxidative stress-induced signaling and toxicity for neurons and oligodendrocytes (McCracken et al., 2000). The GST isoform 4α (GSTA4) helps to overcome the 4-HNE-mediated toxicity and improve the myelination process by reducing the intracellular levels of 4-HNE, increasing the mitochondrial functioning in vitro and in vivo in a demyelination/remyelination model (Carlstrom et al., 2020). The fact that oxidative stress is fundamental in neurological disorders was also confirmed in the experimental autoimmune encephalomyelitis (EAE) mouse model (an autoimmune inflammatory disorder of primary central nervous system demyelination) (Qi et al., 2006). After EAE induction, oxidative damage, impairments in mitochondrial functioning, and compromised mitochondrial network are detected in optic nerves, retinas, brains, and spinal cords (Qi et al., 2006). Consistent with this, mitochondrial dysfunction and increased mitophagy process (which reflect the impairment in the mitochondrial network) have been also unveiled in organotypic brain slice pre-treated with the demyelinating agent, lysolethicin, and in a cuprizone-induced mouse model (often used to investigate the demyelination/remyelination events) (Patergnani et al., 2021c). Although the best-characterized responses induced by SIMH support improved bioenergetics of cells, the importance of this adaptive mechanism also involves the activation of antiapoptotic molecular routes that allow beneficial effects in neuronal survival. One of these is the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is reported to be of primary importance in long-term memory and synaptic changes for brain adaptation to new information. Indeed, as reviewed in (Kaltschmidt and Kaltschmidt, 2015). NF-κB establishes a gene transcription program in favor of neurogenesis, axogenesis, and neuronal transmission in adult brains. Thus, NF-κB results are relevant in AD, where the cognitive ability and memory are lost (Jha et al., 2019), but also in multiple sclerosis (MS) protecting oligodendrocytes against inflammatory insults (Stone et al., 2017). Although not yet proven in models of neurodegeneration, SIMH is reported to be an upstream event in the upregulation of the NF-κB signaling, which triggers the activation of mitochondrial E3 ubiquitin (Ub) protein ligase 1 MUL1, a gene encoding for an E3 Ub transferase located to OMM. The intricate cascade of downstream events would involve the formation of a multiprotein complex composed of: the ubiquitylated form of tumor necrosis factor receptor-associated factor 2, which acts as a bridge between MUL1 and NF-κB; and by the transforming growth factor-β-activated kinase 1, that phosphorylates the NF-κB inhibitors, an inhibitor of nuclear factor kappa B (IKKß) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα), respectively (Zemirli et al., 2014).

Overall, the protective role of SIMH as compensatory fusion under stressful conditions remains to be fully elucidated. Findings suggest that three are the essential components in the evaluation of this mitochondrial stress response from which may belong to either beneficial or detrimental features: what proteins take part in which molecular pathway, the type of stress, and the time duration. About the first one, it would be useful to investigate post-translational modifications of fusion proteins that would occur under stress, and which are almost unknown. About the other issues, currently, a transient event (more difficult to study) would be compensatory and beneficial; a chronic mitochondrial hyperfusion would be deleterious also due to persistent mitochondrial mislocalization in cells and limited mobility (Girard et al., 2012).

The Role of Mitophagy in Neuronal Disorders

Autophagy is a cellular catabolic mechanism, in which cytosolic elements and damaged organelle are sequestered into vesicles (called autophagosomes) and then degraded or recycled through the lysosomes (Klionsky et al., 2021). Autophagy was discovered during the 1960s (Deter et al., 1967), but it was deeply investigated over the past ten years. To date, autophagy is recognized as a molecular mechanism that contributes to preserving cellular homeostasis, confers resistance to undesirable conditions (such as infection, stress, and inflammation), regulates cellular and tissue development, and controls cell fate. Autophagy exists in diverse forms that are specialized to sequester and degrade specific intracellular material. Proteinphagy identifies the involvement of autophagy in the degradation of altered proteins; lipophagy points to the sequestration and removal of lipid droplets; as a result of bacteria or virus infection, xenophagy is activated. In addition to these specialized forms of autophagy, selective forms of autophagy targeting portions or entire organelles, such as ER, nucleus, and peroxisomes, also exist. Among them, the most studied selective autophagic response is mitophagy, a process by which dysfunctional mitochondria are sequestered to be eliminated.

Mitophagy

Under severe or prolonged stress conditions mitochondria fusion is inhibited and occurring fission, which leads to mitochondrial fragmentation to facilitate mitophagy. Mitophagy is a selective cellular mechanism that removes damaged or dysfunctional mitochondria, ensuring the mitochondria quality control (Tajiri et al., 2016). Firstly observed in reticulocytes, mitophagy regulates the cell fate, controlling cellular metabolism and influencing the inflammatory response in several pathological conditions (Patergnani et al., 2021b). The molecular pathway in mitophagy is composed of the axis of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced kinase 1 (PINK1) and Parkin (Kitada et al., 1998). Under normal conditions, PINK1 is continuously kept at low expression levels, thanks to a high-regulated mechanism in which PINK1 is imported into the mitochondria to be degraded. In stressed mitochondria, TIM23/TOM complex activity is corrupted and thus PINK1 accumulates on the OMM. Following a series of phosphorylations (S402, S228, and T257), PINK1 induces Parkin into an active phospho-Ub-dependent enzyme, which determines the ubiquitination of several OMM proteins, including MFN, representing the signal for the recruitment of a series of Ub-binding autophagic receptors, such as the autophagic cargo receptor NBR1, microtubule-associated proteins 1A/1B light chain 3 (LC3), calcium-binding and coiled-coil domain 2 (NDP52), optineurin, tax1-binding protein 1, and p62/Sequestome-1 (Geisler et al., 2010; Pickles et al., 2018).

In these years, mitophagy has acquired more and more value among the NDs, with a role characterized by “lights and shadows” (Doxaki and Palikaras, 2020). Undoubtedly, PD is widely characterized by mutations in the mitophagy regulators, Parkin and PINK1 (Figure 1) (Shefa et al., 2019). To date, more than a hundred autosomal recessive mutations have been unveiled for the Parkin gene, representing the primary cause for the early-onset PD and the common cause of autosomal recessive juvenile parkinsonism. About 130 PINK1 mutations have been characterized and the loss of function mutations represents the second most frequent cause of autosomal recessive PD. Several studies demonstrated that mutated PINK1 and Parkin are responsible to decrease the capacity of the cell to initiate mitophagy (Kitada et al., 1998; Valente et al., 2004a, b; Geisler et al., 2010; Morais et al., 2014; Gautier et al., 2016; Puschmann et al., 2017). Fibroblasts and neurons obtained from patients with PINK1 or Parkin mutations showed impaired recruitment of Parkin on the mitochondrial surface or an altered PINK1 activation (Piccoli et al., 2008; Seibler et al., 2011). However, it has been suggested that the recruitment of Parkin on the mitochondrial surface may occur even in presence of PINK1 mutations. Indeed, suppression of the protease OMA1 (that can import PINK1 into mitochondria for its degradation independently from TIM23/TOM activity and state of mitochondria) restores the mitochondrial accumulation of parkin even in presence of PD-Related PINK1 mutations (Sekine et al., 2019). It also exists mitophagy molecular mechanisms that are PINK1-Parkin independent. Mitophagy may be executed by the OMM protein FUN14 domain-containing protein 1 (FUNDC1). In basal conditions, FUNDC1 is phosphorylated by SRC proto-oncogene, non-receptor tyrosine (SRC) kinase (Liu et al., 2012). Under hypoxia, the dephosphorylated form of FUNDC1, due to SRC inactivation, may associate with LC3 to prompt the incorporation of mitochondria into autophagosomes (Liu et al., 2012). In line with this, NIP3-like protein X (NIX/BNIP3L) is another OMM-resident protein that mediating to specific WXXL-like motif may bind LC3 to sequester mitochondria (Novak et al., 2010; Yuan et al., 2017). Recently, it has been demonstrated that also IMM and matrix resident proteins can modulate mitophagy. Regarding the IMM protein, an example is CL. Upon a mitophagic stimulus, CL moves from the IMM to the OMM where acts as a signal for the identification and removal of damaged mitochondria, since LC3 protein displays CL-binding sites (Chu et al., 2013). Meanwhile, the matrix protein nod-like receptor (NLR) family member NLRX1 has an LC3-interaction region domain that permits the recruitment of LC3 to activate the mitophagy upon infection with the pathogen Listeria (Zhang et al., 2019b).

F1
Figure 1:
Selective mitochondrial autophagic response in neuronal disorders.(A) When mitochondria suffer an important damage, PINK1 accumulates to the mitochondria and recruits Parkin to the OMM. Here, Parkin determines the ubiquitination of mitochondrial resident proteins. This represents a signal for the recruitment of a series of ubiquitin-binding autophagic receptors that promote degradation of the non-functional organelle by mitophagy. Among the diverse neurological disorders, PD is characterized by PINK1-Parkin loss and mutations. These conditions alter the normal PINK1 functioning, thus causing failure in Parkin recruitment on the mitochondrial surface. As a result, the mitochondrial autophagy is impaired and results not efficient to remove damaged mitochondria. (B) Mitophagy is also a key process during AD pathogenesis. Indeed, aberrant production and accumulation of Aβ and tau tangles cause loss of mitochondrial functioning and failure of mitophagy execution. When these conditions persist, neuronal cell death is induced. (C, D) Recent works demonstrate that the circulating markers of mitophagy and mitochondrial dysfunctions are highly expressed in circulating body fluid of MS-affected patients. Interestingly, they correlate to an active phase of the disease. Consistently, the sustained inflammatory condition that characterized MS causes oligodendrocyte damage and loss of mitochondrial functioning, and energetic imbalance. Furthermore, this condition activates the AMPK-dependent autophagy and diverse cellular forms of selective autophagy, such as mitochondrial autophagy and nuclear receptor coactivator 4-ferritinophagy. All these conditions are sufficient to provoke demyelination as well as loss of the re-myelination process. AD: Alzheimer’s disease; AMPK: 5-adenosine monophosphate-activated protein kinase; ANT: adenine nucleotide translocator; ATG: autophagy gene; Aβ: amyloid-beta; MS: multiple sclerosis; Mt: mitochondria; NCOA4: nuclear receptor coactivator 4; NFL: neurofilament; OMM: outer mitochondrial membrane; PD: Parkinson’s disease; PINK1: PTEN-induced kinase 1; WT: wild-type.

Mitophagy involvement in neurodegeneration

In AD brains, it has been observed that Parkin resulted to be depleted over the disease, causing alteration of the normal mitophagic route (Figure 1) (Ye et al., 2015). This determines the accumulation of damaged mitochondria, increased ROS production, reduced ATP production and it may represent a signal for apoptosis and neuronal cell death. The contribution of mitophagy to the PD pathogenesis has been also confirmed in Drosophila, where PINK1-Parkin mutant flies showed mitochondrial alterations, locomotive deficiencies, and defects in neuron development (Julienne et al., 2017). Surprisingly, mice with PINK1 and Parkin deletion did not have evident PD-phenotypes. Indeed, Parkin-deficient mice did not exhibit profound deficits in neurological function, learning, memory and the substantia nigra pars compacta dopamine neurons were unharmed (Perez and Palmiter, 2005). A similar observation was achieved in PINK1 knock-out (KO) mice, where the number and the morphology of dopaminergic neurons in the substantia nigra were comparable with the wild-type mice (Kitada et al., 2007). PINK1 KO mice only exhibited a modest deficit in locomotor activity and increased inflammation following exhaustive exercise, which severely stressed mitochondria (Kelm-Nelson et al., 2018; Sliter et al., 2018). Despite this, the levels of pro-inflammatory cytokines in the serum of PINK1 KO mice, in resting conditions were comparable to those in wild-type mice (Sliter et al., 2018). Overall, these data suggest that compensatory mechanisms are activated to preserve the neuronal homeostasis, and the fact that PINK1 and Parkin did not induce robust PD-phenotype, indicates that PINK1-Parkin mitophagic pathway under physiological circumstances may be dispensable. Opposite, the PINK1-Parkin axis became essential in response to pathological stimuli or stress conditions. In confirmation of this, by crossing Parkin KO mice with a mouse model that accumulates altered mitochondria (Mutator mice), the mitochondrial dysfunctions exacerbated and lead to dopaminergic neuronal cell death, phenotypes not observed in the parental Mutator or Parkin-KO (Pickrell et al., 2015).

In AD, the neuronal loss is due to uncontrolled protein accumulation of amyloid-β (Aβ), alpha-synuclein (α-syn), Ub, and APOE, which form aggregates of extracellular (amyloid) plaques; and of APOE and hyperphosphorylated tau, responsible for intracellular and extracellular neurofibrillary tangles, respectively. In the last years, several reports suggest that mitophagy represents the main process for AD progression. Aβ, amyloid precursor protein, and its processing enzymes were found to provoke alterations in mitochondrial morphology and function, with failing in mitophagy activation. Notably, this effect was unveiled in vitro as well as in the AD mouse model and also in the human post-mortem brain, where the accumulation of altered mitochondria was associated with mitophagy failure (Vaillant-Beuchot et al., 2021). Furthermore, in AD brains, it was also observed that Parkin resulted to be depleted over the disease, causing alteration of the normal mitophagic route with consequent loss of mitochondrial functions (Ye et al., 2015). Defects in mitophagic activity were also reported in the recent work of Fang et al. that unveiled evidence of mitophagy impairment in the hippocampus of AD patients, in neurons derived from induced pluripotent stem cells, in diverse AD animal models, and Aβ Caenorhabditis elegans (C. elegans) models (Fang et al., 2019). However, using the NAD+ precursor, nicotinamide mononucleotide, as mitophagic inducer, the cognitive impairments were ameliorated (Fang et al., 2019). Indeed, the overexpression of PINK1 reduced Aβ accumulation and counteracted the cognitive impairments, improving synaptic function and learning memory in AD animal models, through the NDP52- and optineurin-dependent mitophagy (Du et al., 2017). Altered expression of autophagic and mitophagy markers has been observed in biofluids obtained from AD patients, changes that could be used as possible biomarkers for an early detection or monitoring of progression disease (Castellazzi et al., 2019b).

N-terminal truncation of tau protein represents another hallmark of AD and occurs as an early event in the disease (Garcia-Sierra et al., 2008). It has been demonstrated a stable association between an N-terminal fragment of tau with Parkin, correlated to cognitive impairments in AD animal models as well as in the human AD brain (Corsetti et al., 2015). This protein interaction blocked the recruitment of Parkin on the mitochondrial membrane, determining impairments in mitophagy (Cummins et al., 2019).

Disarrangements in mitochondria quality control have been observed also in MS. 5-adenosine monophosphate-activated protein kinase (AMPK) is the primary activator of diverse selective autophagy responses, including mitophagy. It has been demonstrated that MS-like conditions determined myelin loss with a concomitant change in the energetic status of oligodendrocyte and loss of several mitochondrial functions, which provoked ROS production and triggered autophagy by AMPK activation (Bonora et al., 2014b). The fact that a deregulated mitochondrial status is determinant to trigger autophagy in MS was also demonstrated in vivo in various MS animal models (Alirezaei et al., 2009; Joubert et al., 2009; Akatsuka et al., 2017; Becher et al., 2018; Paunovic et al., 2018). However, these studies lack to demonstrate that the mitophagy process is directly involved in MS pathogenesis. First evidence was achieved when circulating markers of mitophagy were found in both sera and cerebrospinal fluid (CSF) of MS patients (Figure 1) (Patergnani et al., 2018). Interestingly, they correlated with the active phase of the disease and with the release of pro-inflammatory cytokines (Castellazzi et al., 2019a). Other clinical studies confirm this first study, elevated circulating levels of Parkin, ATG5, neurofilament light chain (an adverting biomarker of axonal damage) and reduced levels of mitochondrial adenine nucleotide translocase 1 were detected in biofluids of MS patients (Hassanpour et al., 2020; Joodi Khanghah et al., 2020). All these findings, not only suggest a sustained activation of the mitochondrial quality control program aimed to remove the altered mitochondria during MS, but also propose circulating mitophagic proteins as potential predictive biomarkers. However, before this, it is necessary to validate these observations in greater patient cohorts and monitor the expression of autophagy and mitophagy markers during the active treatments used against MS. In addition, it is of fundamental importance to understand the origin of these markers and verify whether they may be only the result of cell death events that occur in MS. In these studies, the authors lack to investigate these critical points and translate their findings into other experimental models. A deeper investigation of the role of mitophagy in MS comes from our recent study (Patergnani et al., 2021c). Here, we confirm the excessive presence of mitophagy markers in both CSF and sera of MS patients. Indeed, we demonstrated the direct activation of mitophagic machinery in an in vivo demyelinating mouse model. Our results have also translational potential since we show that blocking the abnormal mitophagy with anti-psychotic compounds (identified as potential inhibitors of autophagy) permitted the reactivation of myelination in vivo. Finally, we uncovered that apart from mitophagy, also the selective ferritin-autophagy, mediated by the nuclear receptor coactivator 4, was responsible to prompt the inflammatory response in all MS models analyzed (Figure 1) (Patergnani et al., 2021c). These findings show that mitophagy acts as a secondary mechanism that exacerbates the progression of pathology, becoming a novel potential therapeutic target against MS.

Similar considerations should be done also for epilepsy, where several studies have demonstrated that impairment in mitochondrial functions is critical for the development and progression of the disease, and these mitochondrial dysfunctions are accompanied by persistent mitophagy (Rahman, 2015). Mediating TEM analysis, it has been observed the accumulation of autophagosomes and damaged mitochondria in tissue samples from hippocampi and temporal lobe cortexes of refractory temporal lobe epilepsy patients (Wu et al., 2018). To date, it has been demonstrated that glutamate-induced excitotoxicity caused neuronal death in epilepsy (Ambrogini et al., 2019), influencing also the mitophagy functioning (Jin et al., 2018; Wang et al., 2019a). It was observed that glutamate-induced excitotoxicity activated mitophagy in mouse hippocampal neurons. The maintenance of an adequate level of mitochondria was performed by administration of melatonin and leptin, which reduced mitophagy and neuronal cell death. Similarly, persistent mitophagy and neuronal degeneration were observed in different status of epileptic rat models (Zhang et al., 2020b).

Protective or detrimental? The role of mitophagy in neuronal disease is controversial; its cytoprotective effect is questioned by the persistence activation of the process that exacerbates its action contributing to neuronal vulnerability.

The Role of Mitochondrial Unfolded Protein Response (UPRmt) in Neuronal Disorders

UPRmt was originally identified in mammals but it is thanks to studies in C. elegans that the genes involved in sensing and responding to this mitochondrial stress response have been identified (Martinus et al., 1996). Oxidative phosphorylation dysfunction, proteostatic stress, ATP depletion, dissipation of mitochondrial membrane potential, and pathogen infections play a key role in the UPRmt activation (Yoneda et al., 2004; Haynes and Ron, 2010). Findings permitted to identify in the proteins ubiquitin-like 5, Homobox protein dve-1, and stress-activated transcription factor (ATFS-1) the essential members of UPRmt in C. elegans. In mammals is activating transcription factor 5 (ATF5), the homologous to ATFS-1, the principal actor of UPRmt, where its expression is influenced by the transcription factors C/EBP homologous protein (CHOP) and ATF4, respectively (Quiros et al., 2017). Differences among C. elegans and mammals are not only restricted to this, indeed in mammals, but UPRmt is also part of a broader stress response program called the integrated stress response. During this adaptive translational program, stress stimuli activate four kinases, which activities converge on phosphorylation of the eukaryotic initiation factor 2. It has been demonstrated that integrated stress response responds to the mitochondrial dysfunction and participates with UPRmt to the recovery of mitochondrial homeostasis (Fessler et al., 2020; Guo et al., 2020). Furthermore, eukaryotic initiation factor 2 phosphorylation increases translation of ATF4 (Guo et al., 2020), indicating integrated stress response as an essential mechanism to sustain the UPRmt activation, mediating ATF5. In the next section, we describe the molecular mechanisms of UPRmt and report how these are involved in NDs.

Mechanisms and function of UPRmt

UPRmt is a protective mitochondrial to the nuclear signal response that involves a set of transcription factors, which up-regulate nuclear gene expression to induce mitochondrial chaperones, proteases, and antioxidant enzymes to reduce the protein-folding burden of the organelle or remove toxic proteins. Array analysis revealed that UPRmt also induces the transcription of mitochondrial fission, metabolic, biogenesis, inflammatory, and mitokine genes (Aldridge et al., 2007; Nargund et al., 2012; Tian et al., 2016; Yi et al., 2018). It is activated in response to alterations of mitochondrial proteostasis, variations of membrane potential caused by various stress conditions, such as oxidative, metabolic stress, protein folding or import defects, and mtDNA alteration (Houtkooper et al., 2013; Moehle et al., 2019).

To date, independent and parallel pathways are linked to UPRmt. The first one involves the transcription factor CHOP, which promotes the transcription of mitochondrial proteases and chaperons, such as ATP-dependent Clp protease proteolytic subunit (CLPP) and the heat shock protein 60 (HSP60), in response to proteotoxic stress through the transcriptional regulator ATF5 (Zhao et al., 2002; Fiorese et al., 2016). ATF5 has a mitochondrial localization and nuclear targeting sequence, which under physiological conditions it is constitutively imported and degraded into mitochondria (Teske et al., 2013; Harbauer et al., 2014; Fiorese et al., 2016). When a mitochondrial stress condition occurs, the mitochondrial translocation of ATF5 is blocked, resulting in its relocalization to the nucleus, where activates the transcription of UPRmt marker genes, like HSP60 and CLPP (Haynes and Ron, 2010; Nargund et al., 2012; Rolland et al., 2019).

The other two UPRmt activating ways are CHOP-ATF5 independent. In the estrogen receptor alpha (ERα) pathway, ROS production induces the AKT phosphorylation and the subsequent ER-α activation with the induction of the intra-mitochondrial-space protease htrA serine peptidase 2, the mitochondrial biogenesis regulator NFR1 and the increase in proteasome activity (Papa and Germain, 2011). In the Sirtuin 3-axis, forkhead box O activation induces the expression of the antioxidant superoxide dismutase (SOD)-1, -2, and catalase genes as well as mitochondrial biogenesis and mitophagy genes (Papa and Germain, 2014; Kenny and Germain, 2017).

The emerging role of UPRmt in neurodegeneration

Differently from other mitochondrial stress responses, the role of UPRmt in neuronal diseases is emerging, where ATF5 (in mammalian) or ATFS-1 (in C. elegans) pathways seem to have significant implications. Regarding PD, analysis of the postmortem brain revealed enhanced levels of UPRmt activation markers, such as HSP60 (Pimenta de Castro et al., 2012). Parkinsonian toxins used in PD models, including inhibitors of mitochondrial complex I and enhancers of ROS production, are considered potent UPRmt inducers (de Castro et al., 2011). Consistent with this, the proteostatic stress induced by the aggregation in the mitochondrial compartment of the highly soluble unfolded protein α-syn, which accumulates in Lewy bodies and Lewy neurites in PD and other synucleinopathies, represents a critical step in the recruitment of UPRmt (Franco-Iborra et al., 2018). Accumulation of α-syn in mitochondria, imported by specific interaction with TOM20, has been reported in substantia nigra pars compacta of PD patients (Devi et al., 2008; Di Maio et al., 2016). It has been demonstrated that the α-syn PD-related variant A53T, accumulating into the mitochondria, inhibits the UPRmt peptidase marker, CLPP, which sustained the UPRmt activation over time with detrimental effects in dopaminergic neurons (Hu et al., 2019). Abnormal UPRmt activation has been also obtained in the C. elegans model of PD overexpressing the α-syn PD-related variants, A53T and A30P, conditions in which the beneficial effects of UPRmt are lost when persisting the UPRmt-overactivation inducing neurotoxic consequences (Martinez et al., 2017). The overexpression and overactivation of ATFS-1 potentiate the proteotoxicity of α-syn in dopaminergic neurons, demonstrating that UPRmt overactivation contributes to exacerbating the pathogenesis in PD (Martinez et al., 2017). However, the survival of dopaminergic neurons is initially subjected to ATFS-1 and UPRmt activation, as shown in C. elegans mutants for mitochondria-related genes implicated in monogenic PD (Cooper et al., 2017). The accumulation of dysfunctional mitochondria in pdr-1 and pink-1 mutants led to the activation of UPRmt. In this case, ATFS-1 was required for the longevity of PD mutants and mitigated the detrimental effects of mutants on the dopamine neurons (Cooper et al., 2017). These two facets of the same pathway suggest that ATFS-1-dependent UPRmt activation is potentially a hermetic process: beneficial during transient activation, but detrimental during chronic activation.

Aβ deposits in the brain are also present in mitochondria of AD mice and patients (Caspersen et al., 2005). Aβ precursor is cleaved by the mitochondrial HtrA2 protease, which controls the Aβ oligomerization delaying its proteotoxic effect (Park et al., 2006; Kooistra et al., 2009). Like in PD, the proteotoxic effect of mitochondrial Aβ activated UPRmt in human cells and mice (Shen et al., 2019). However, the Aβ-induced proteinopathy was exacerbated by pharmacological inhibition of UPRmt, indicating that also in AD the UPRmt has initially a protective role (Perez et al., 2020). Prefrontal cortex derived from AD patients presented high expression levels of UPRmt-induced genes, such as mitochondrial chaperone HSP60 and ATP-dependent zinc metalloprotease YME1L, which correlated with an increase in severity of disease (Beck et al., 2016; Sorrentino et al., 2017).

Oxidative and proteostatic stresses play a key role in the activation of UPRmt also in amyotrophic lateral sclerosis (ALS) and a spectrum of TDP-43-related proteinopathies, such as frontotemporal lobar degeneration (Gomez and Germain, 2019; Wang et al., 2019c). Mutations in mitochondrial SOD1 are one of the principal causes of ALS, where the paralysis due by damages of motor neurons and the spinal cord is a consequence of increased production of ROS (Beckman et al., 2001) and abnormalities in multiple organelles in neurons, including mitochondria (Magrane et al., 2014). In particular, the mutant SOD1G93A accumulates in mitochondria in vivo, on the OMM, where interacts with apoptotic-regulating proteins and/or Ca2+-effector proteins, such as B-Cell Lymphoma 2 (BCL2) and voltage-dependent anion-selective channel, respectively (Israelson et al., 2010; Pedrini et al., 2010). Furthermore, SOD1G93A may also accumulate in the IMS, where alter the import and maturation of mitochondrial proteins, thus promoting mitochondrial fragmentation and alterations in mitochondrial dynamics in motor neurons (Kawamata and Manfredi, 2010; Igoudjil et al., 2011). The oxidative and proteostatic stress, activating UPRmt in ALS, is also sustained by mutated TDP-43 and CHCHD10 (coiled-coil-helix-coiled-coil-helix domain containing 10), which accumulate into mitochondria, induce ROS production, mitochondrial dysfunction, and the up-regulation of UPRmt-related transcription factors CHOP and ATF5 in vivo (Anderson et al., 2019; Wang et al., 2019c; Straub et al., 2021). The activation of UPRmt has a protective role in the onset of ALS, but its function may exacerbate the disease progression causing neurodegeneration, as demonstrated by the abnormal accumulation of mitochondrial TDP-43 due to the downregulation of mitochondrial LONP1 protease. In addition, UPRmt activation may be conditioned by sex difference, as emerged in SOD1G93A mutant mice (Riar et al., 2017; Pharaoh et al., 2019; Wang et al., 2019c).

Proteostatic effects have been also associated with mutant huntingtin although to date it is not reported a direct involvement in active UPRmt. Huntingtin impairs the mitochondrial protein import, localizing to mitochondria in vitro and in vivo in HD models and the caudate nucleus of HD patients (Orr et al., 2008; Yano et al., 2014). ATF5 accumulation has been reported within the characteristic polyglutamine-containing neuronal nuclear inclusions in the brains of HD patients and mice (Hernandez et al., 2017). In the HD model, the overexpression of ATF5 mitigated the neurotoxicity induced by self-aggregating poly-glutamine, suggesting that UPRmt and ATF5 have a protective role in HD. On the contrary, the sequestration of ATF5 into polyglutamine-containing neuronal nuclear inclusions seems to abolish its neuroprotective activity, rendering the neurons more susceptible to mutant huntingtin-triggered death. High levels of ATF5 have been also found in adult neurons of epilepticus mice and were correlated as a pro-survival mechanism (Torres-Peraza et al., 2013).

In these years, the relationship between UPRmt and neuronal diseases is growing, generally considered as beneficial for cellular homeostasis; however, evidence has started to reconsider this mitochondrial response, showing that the abnormal UPRmt activation may be detrimental to the cell under some pathological conditions.

The Role of “Mito-inflammation” in Neuronal Disorders

Relationship between inflammation and mitochondria: the mito-inflammation concept

Chronic neuroinflammation is a common implication of NDs, characterized by microglia and/or astrocytes activation, which provoke an increased release of cytokines or chemokines and in some cases disruption of the blood-brain barrier with infiltration of immune cells. A process may be induced by mitochondrial dysfunction that, in turn, may promote and exacerbate the mitochondrial damage (Lin and Beal, 2006; Bader and Winklhofer, 2020). This vicious cycle leads to the release of mitochondrial damage-associated molecular patterns (mtDAMPs), such as mtDNA, ROS, Ca2+, CL, and other mitochondrial-derived molecules, in part following a vesicle pathway, which activates specific inflammatory cascades. mtDAMPs, in turn, play a key role in several inflammatory-related pathological conditions, including the NDs (Lezi and Swerdlow, 2012; Swerdlow, 2012; Patergnani et al., 2021a) (Figure 2).

F2
Figure 2:
Contribution of mito-inflammation in neuronal disorders.Dysfunctional mitochondrial in neuronal and in infiltrated cells through the blood-brain barrier release mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (ROS), ion calcium (Ca2+), and cardiolipin (CL) to sustain the neuroinflammation in neuronal disorders. The mito-inflammation is the contribution of the organelle to inflammatory response, when mitochondrial constituents and products are released to induce the up-regulation, activation, and release of inflammasomes and pro-inflammatory mediators, respectively. Created with BioRender.com.

Involvement of mito-inflammation in neurodegenerative diseases

The high susceptibility to mitochondrial alterations observed in NDs render the cells of the system nervous more prone to detrimental effects of mito-inflammation. Mito-inflammation is the mitochondrial compartmentalization response of inflammation, mediated by recognition of mtDAMPs from pattern recognition receptors that may be expressed by microglia, astrocytes, and macrophages (Lampron et al., 2013; Walsh et al., 2014; Freeman et al., 2017), but also by oligodendrocytes (McKenzie et al., 2018), neurons (Kaushal et al., 2015) and endothelial cells (Gong et al., 2018). mtDAMPs may be released outside the cell following a specific vesicle pathway, where mitochondrial-derived vesicles are generated through the selective incorporation of protein cargoes, which may include outer, inner membrane, and matrix content (Neuspiel et al., 2008; Soubannier et al., 2012). Findings indicate that mitochondrial-derived vesicles-mediated transfer of mitochondrial content, such as oxidized mtDNA or mitochondrial proteins, influences the inflammatory responses of recipient cells, although the effect can be either anti- or pro-inflammatory, depending on the context (Todkar et al., 2021). Encapsulated mitochondria-derived constituents released from microglia, in the genetic mouse model of ND, contribute to disease propagation by acting as effectors of the innate immune response, targeting adjacent astrocytes and neurons (Joshi et al., 2019). The immune stimulation by mitochondrial-derived vesicles can also occur in absence of inflammation, as in the case of the priming of dendritic cells mediated by antigen-driven activated T lymphocytes through the transferring of mtDNA to induce protection of dendritic cells against pathogen infection (Torralba et al., 2018).

In the post-mortem brain of PD patients, the deficit of complex I observed in platelets and fibroblasts represent the principal cause of mitochondrial ROS production, responsible for oxidative damages, even at the mtDNA level (Yoshino et al., 1992; Haas et al., 1995; Keeney et al., 2006; Villace et al., 2017). Oxidized and degraded mtDNA was found in human CSF plasma and mouse primary astrocytes associated with inflammatory and neurodegeneration states (Mathew et al., 2012). Circulating mtDNA was found increased also in CSF subjects with traumatic brain injury and correlated with unfavorable neurological outcomes (Walko et al., 2014). The level of circulating mtDNA is thus a potential biomarker for early-stage of PD and AD disease (Podlesniy et al., 2013; Pyle et al., 2015). Evidence of oxidative mtDNA modifications is present also in AD patients (Mecocci et al., 1994; Lovell and Markesbery, 2007). Consistent with this, external mtDNA injection into rodent hippocampi induced pro-inflammatory changes, increasing the levels of phosphorylation of pro-inflammatory transcription factors in the cortex (Wilkins et al., 2016). In particular, the authors observed an increased expression of the cell surface colony-stimulating factor 1 receptor, which promoted AKT phosphorylation that, in turn, activated NF-κB signaling (Wilkins et al., 2016). Interestingly, the authors also validated their findings in an AD mouse model, thereby demonstrating how mitochondria and/or mitochondrial fragments may contribute to neuroinflammation.

Mitochondrial-derived ROS, primarily produced from complex I and III due to accumulation of unfolded proteins, excessive Ca2+ or oxidative phosphorylation impairment, activate the NF-κB pathways, first signal (priming) of inflammasome activation. This results in the transcriptional upregulation of inflammasome members and cytokines, such as NLR family pyrin domain containing 3 (NLRP3) and interleukin 1β (IL-1β) (Figure 2) (Rubartelli, 2014; Chen et al., 2015; Rimessi et al., 2016; Patergnani et al., 2021a). Perturbations in mitochondrial Ca2+ signaling contribute to boosting the production of mitochondrial ROS with important repercussions on the inflammatory status (Figure 2) (Rimessi et al., 2015). This may happen directly, by stimulating mitochondrial ROS-generating enzymes, such as α-ketoglutarate and glycerol 3-phosphate dehydrogenase (Murphy, 2009; Gorlach et al., 2015), or indirectly, mediating the Ca2+-dependent activation of nitric oxide synthase, which blocks the mitochondrial complex IV via nitric oxide and through the Ca2+-dependent mitochondrial membrane depolarization via reverse electron transport (Biasutto et al., 2016).

The mitochondrial ROS is also involved in NLRP3 inflammasome activation in SOD1G93A mutant mice-derived microglia, where the protein aggregates have an essential role to induce mitochondrial dysfunction in ALS (Deora et al., 2020). NLRP3 is an emerging pattern recognition receptor, a key player in neuroinflammation, activated by mitochondrial ROS, mtDNA, cardiolipin, and Ca2+ in a two-step process (Figure 2). It accumulates to mitochondria where oligomerizes with apoptosis-associated speck-like protein containing a CARD (ACS) and pro-caspase (CAS)-1 to promote the release of IL-1β and IL-18 (Rimessi et al., 2015; Zhong et al., 2018). Mitochondrial cardiolipin that is regulated by the transcriptional activity of ATFS-1 (Shpilka et al., 2021) is also required for NLRP3 inflammasome activation (Figure 2). Indeed, exposure to the antibiotic linezolid provoked mitochondrial dysfunction and activated NLRP3. Interestingly, inflammasome activation and mitochondrial damage were abolished when the mitochondrial compartment was stabilized with the inhibitor of mitochondrial membrane permeability transition cyclosporine-A, thereby suggesting a close relationship between inflammasome recruitment and mitochondria activities. This was confirmed since the authors not only demonstrated that NLRP3 can bind CL, but they also provided evidence that CL is required for NLRP3 activation and its docking to mitochondria (Iyer et al., 2013). CL is downregulated in PD and AD brain, it is frequently found peroxided by the increased oxidative stress that characterizes these pathologies, influencing its regulatory activity on the mitochondrial respiration complex (Ruggiero et al., 1992; Chicco and Sparagna, 2007; Tyurin et al., 2008; Monteiro-Cardoso et al., 2015). In particular in PD pathogenesis, CL interacts with α-syn within the mitochondrial membranes of PD brains, and this protein interaction interferes with the ability of cardiolipin to regulate the electron transport chain, exacerbating the progression of PD through the production of mitochondrial ROS (Shen et al., 2014; Ghio et al., 2016).

NLRP3 activation has been implicated in the progression of several neuronal disorders. Genetic polymorphisms of NLRP3 and high levels of systemic and localized NLRP3 inflammasome expression, such as in mesencephalic neurons, are associated with the progression of the disease and motor severity (von Herrmann et al., 2018; Fan et al., 2020). The recruitment of inflammasome was also confirmed by high levels of IL-1β and CAS-1 measured in serum and striata of PD patients, respectively (Mogi et al., 1994; Zhou et al., 2016).

α-Syn may active the NLRP3 inflammasome in human monocytes and stabilized microglial cells, while the failure in NLRP3 activation in primary microglial cells remains controversial (Gustin et al., 2015; Gustot et al., 2015; Zhou et al., 2016). The inflammasome activation in primary microglia is instead mediated by mitochondrial dysfunction and by the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which via mitochondrial ROS led to NLRP3 assembly to induce dopaminergic neurodegeneration (Sarkar et al., 2017; Lee et al., 2019). A contribution to neurodegeneration is also promoted by the negative regulation of autophagy-mediated by NLRP3 inflammasome activation in microglia. Autophagy fails to clear protein aggregates and damaged organelles conditioning the immune responses and neuroinflammation, as reported in prion diseases. Here, it was demonstrated that the neurotoxic prion peptide PrP106-126 activates NLRP3 in a murine microglial cell line, which in turn, promoted CAS-1-induced TIR-domain-containing adapter-inducing interferon-β cleavage. In this state, TIR-domain-containing adaptor-inducing interferon-β fails to activate autophagy (Lai et al., 2018). In line with this finding, the exacerbation of NLRP3 inflammasome activation has been reported in Parkin and PINK1 KO mice- and patients-derived microglia, where the abnormal NLRP3 signaling was also associated with downregulation of the negative regulator of NF-κB, A20 protein (Mouton-Liger et al., 2018). Indeed, the administration in PD-induced rat models of CAS-1 inhibitor, Ac-YVAD-CMK, or the Cyclosporine A derivate, NIM811, improved the number of dopaminergic neurons reducing the activation of NLRP3 inflammasome (Mao et al., 2017; Zhang et al., 2020a).

The deposition of misfolded Aβ is the pivotal cause of NLRP3 inflammasome activation in microglia in AD pathology. Aβ may bind ASC, released from inflammasome activation, exacerbating the formation of Aβ oligomers (Holbrook et al., 2021). Also, tau protein oligomers contribute to NLRP3 inflammasome in human microglial cells (Panda et al., 2021). Microglia with elevated expression of IL-1β have been detected surrounding Aβ plaques in AD patients (Simard et al., 2006). Besides microglia also peripheral blood mononuclear cells isolated from AD patients presented higher expression levels of NLRP3 inflammasome members, such as NLRP3, ASC, CAS-1, and the cytokines IL-1β and IL-18, indicating that also the peripheral NLRP3-signal is increased in AD (Saresella et al., 2016). Similar findings were observed in both peripheral blood mononuclear cells and CSF of MS patients, in which high levels of IL-1β and IL-18 have been reported, indicating a sustained NLRP3-activating signal (Inoue and Shinohara, 2013). The expression of gain-of-function variants of NLRP3 (Q705K) and IL-1β (-511C>T) correlated with severity and progression of MS, indicating that a sustained activation of the inflammasome is associated with a bad prognosis of MS (Soares et al., 2019). Indeed, CAS-1 and ASC have been suggested as biomarkers for MS onset, since elevated expression of CAS-1 has been found at demyelinating lesions levels (Keane et al., 2018; Voet et al., 2018). However, the cognitive impairments and the neuropathology ameliorated when inflammasome was inhibited, as demonstrated by administration of MCC950 or by CAS-1 inhibitor, VX-765, that improved the cognitive function and neuroinflammation in AD mouse models, limiting the deposition of Aβ plaques and favoring their clearance (Dempsey et al., 2017; Flores et al., 2018). The pharmacological inhibition of NLRP3 has shown good results also in EAE and stroke mice models. Indeed, by suppressing the inflammasome activation the severity of the pathologies was attenuated and the clinical outcomes ameliorated (Coll et al., 2015; Ismael et al., 2018). To date, only very few compounds targeting NLRP3 or CAS-1 have entered clinical trials. RP-1127, an NLRP3 inflammasome inhibitor (Lamkanfi et al., 2009) has been tested in a clinical trial for stroke (EudraCT 2017-004854-41) and traumatic brain injury (ClinicalTrials.gov: NCT01454154), after positively evaluated pilot studies (Sheth et al., 2014a, b).

NLRP3 is not the only inflammasome to be associated with mitochondria, continuous findings indicate that NLRC4 (NLR family CARD Domain Containing 4), AIM2 (Interferon-inducible protein AIM2), and NLRP1 (NLR Family Pyrin Domain Containing 1) are also linked to mitochondrial dysfunction and appear to play a key role in neuronal diseases. High expression levels of NLRC4 and AIM2 have been observed in neuronal tissue of sporadic AD patients and mutant SOD1 transgenic animals, respectively (Liu and Chan, 2014; Johann et al., 2015; Gugliandolo et al., 2018). Elevated levels of NLRP1 have been found in traumatic patients with brain injury and in mice with spinal cord injury (de Rivero Vaccari et al., 2008; Adamczak et al., 2012; Wallisch et al., 2017). NLRP1 was significantly increased in the brain of AD patients, its genetic variants are associated with the risk of AD, when genetically modulated in an AD mouse model the cognitive impairments and the neuronal pyroptosis were attenuated (Pontillo et al., 2012; Tan et al., 2014; Kaushal et al., 2015).

In contraposition to inflammasomes, the mitochondria-located innate immune sensor NLRX1 inhibits different pro-inflammatory pathways, such as the NF-κB signaling, to control the microglial activation and the generation of neurotoxic astrocytes, thus preventing the neuroinflammation and the death of neurons and oligodendrocytes (Xia et al., 2011; Imbeault et al., 2014; Killackey et al., 2019). NLRX1 mediated the protection against EAE in a murine model of MS, repressing the inflammation induced by macrophages and microglia (Eitas et al., 2014). The protective role of this NLR receptor in the progression of the disease is supported by the several mutations identified in MS patients, which correlate with an exacerbated clinical outcome (Chen et al., 2021).

The compartmentalization response of neuroinflammation associated with mitochondria is thus mainly correlated to the release of mtDAMPs and by inflammasomes activation in the innate immune brain cells, where the high levels of inflammatory cytokines secreted condition the cell survivor of resident cells (Heneka et al., 2018). The quantity of cytokines released from activated microglia increases about six times more in the AD brain, and a similar secretion has been quantified also in other ND (Griffin et al., 1989; Hunot et al., 1999). However, in brain cells, the expression of receptors for IL-1β and IL-18 is highly related to the cognitive, learning, and memory processes. This suggests that a fine regulation is necessary as the therapeutic target (Tsai, 2017). Treatments with IL-1β neutralizing antibodies or with IL-1 receptor antagonists, such as anakinra, improved the cognitive and motor outcomes in traumatic brain injury and the ALS mouse model (Clausen et al., 2009; Bertani et al., 2017). Surprisingly, anakinra did not show improvements in human ALS patients and the deletion of IL-18 did not protect the AD mice from neuropathy but developed a lethal seizure disorder that was reversed only by anticonvulsants, to confirm the complexity of the physiopathology associated with neuroinflammation (Maier et al., 2015; Tzeng et al., 2018).

The Role of Apoptosis in Neuronal Disorders

Programmed cell death describes a series of different genetically encoded mechanisms that are responsible for the target and destruction of irreversibly damaged cells. These cellular processes are fundamental to human tissue development and are critical for the correct maintenance of organismal homeostasis. Historically, and accordingly, to the macroscopic morphological alterations, programmed cell death was classified into three isoforms: type I cell death or apoptosis, type II cell death or autophagy, and type III cell death or necrosis (Galluzzi et al., 2007). To date, this nomenclature has been extended and there are at least 20 distinct cell death types (Galluzzi et al., 2018). Nevertheless, apoptosis remains the most studied and relevant cell death for both physiological and pathological conditions. In the following sections, we will give a general overview of the apoptotic process and describe its involvement in NDs.

A brief overview of the apoptotic process

Mitochondria have a recognized role in regulating cell apoptosis being the leading actors of the apoptotic intrinsic cascade (Galluzzi et al., 2016; Patergnani et al., 2020b). The loss of membrane integrity induces the release of IMS-resident pro-apoptotic factors into the cytosol, such as the second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) and cyt-c (Rasola and Bernardi, 2011; Giorgi et al., 2012). Once in the cytosol, cyt-c interacting with CAS-9 and the cofactor apoptosis protease-activating factor (APAF) forms the “apoptosome” that in turn activates the effector caspases, triggering the apoptotic machinery (Bonora et al., 2014a). In this context, Ca2+ has a pivotal role. Within the cell, the average Ca2+ concentration is very low. However, a series of so-called intracellular Ca2+ stores, including ER, present high concentrations of Ca2+. It has been demonstrated that following ER stress, oxidative damage, and/or chemotherapy promote a massive Ca2+-release from the ER into the cytoplasm that is sufficient to activate a class of cysteine proteases (calpains), which can trigger the caspase activation. In addition, the close juxtaposition between ER and mitochondria potentiates the Ca2+-transfer from ER to the mitochondrial matrix to promote mitochondrial permeability transition, mitochondrial swelling, thereby activating the apoptotic cascade (Giorgi et al., 2018).

Apoptosis and neurodegeneration

Apoptosis is a key process for the normal development of the brain and the spinal cord as well as it is crucial for the construction of an efficient neuronal network. The main components of the apoptotic machinery have been found to be crucial for the regulation of neuronal cell death. APAF1–/– mice die before birth, due to impaired apoptosis, as demonstrated by the presence of enlarged brains (Cecconi et al., 1998). Downregulation of the anti-apoptotic gene BCL-XL results to be lethal during gestation (Los et al., 2002). The analysis of embryos revealed excessive apoptotic levels in immature neurons of the spinal cord, brain, and dorsal root ganglia. In line with this, BAX deficiency provokes excessive neurogenesis and consequent formation of medulloblastoma (Garcia et al., 2015). Meanwhile, these findings highlight the importance of apoptosis during neural developments, several other studies demonstrate that excessive apoptosis has the main role in neurodegeneration, due to the massive presence of mitochondrial dysfunction among the cells of the nervous system (Figure 3). The characteristics of motor symptoms, occurring in PD, mainly come from dopamine depletion caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Apoptosis has been implicated as the predominant mechanism of neuronal death in PD, as indicated by postmortem studies in dopaminergic neurons of PD patients (Hartmann et al., 2000; Mogi et al., 2000; Tatton, 2000). Apoptosome formation occurs in the substantia nigra and locus ceruleus in PD brains (Kawamoto et al., 2014). Among pro-apoptotic proteins involved in PD, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, BAX has been shown to exert a pivotal role in substantia nigra pars compacta dopaminergic neuronal death, likely by acting in injured neurons before the onset of irreversible cell death events (Vila et al., 2001). At the demonstration, MPTP injection increases the expression of BAX and decreases the BAX-BCL2 ratio, thereby provoking apoptotic neuronal death. In line with this, BAX-deficient mice are resistant to MPTP-induced neuronal death (Vila et al., 2001). Furthermore, pre-administration of BAX-inhibiting peptides decreased the loss of the nigral dopaminergic neurons in the 6-hydroxydopamine-induced PD rat model and targeting BAX, by the microRNA-216a, inhibited neuronal apoptosis in a cellular PD model (Ma et al., 2016; Yang et al., 2020). Interestingly, the α-syn accumulation and cyt-c could develop a deleterious loop in the surviving dopaminergic neurons. Cyt-c contributed to α-syn radical formation and oligomerization as demonstrated in a pesticide-induced model of PD (Kumar et al., 2016). Indeed, co-exposure to pesticides, such as maneb and paraquat, induced the release of cyt-c into the cytosol. Here, cyt-c co-localizes with α-syn to induce its oligomerization and the protein radical formation in the midbrain of mice treated with maneb and paraquat (Kumar et al., 2016). Furthermore, it has been shown that α-syn localizes on the mitochondrial surface, where induces oxidative stress causing the release of cyt-c triggering mitochondria-mediated apoptosis (Figure 3) (Parihar et al., 2008). Therapeutic strategies focused on targeting antioxidant and apoptotic pathways are gaining increasing importance in PD. For example, in the PD model 6-OHDA-induced apoptosis, the addition of the flavone tricetin provided neuroprotection by down-regulating BAX, up-regulating the anti-apoptotic protein BCL2, mitigating mitochondrial membrane potential loss, and protecting cells from mitochondria-dependent apoptotic pathway (Ren et al., 2019). In a PD rat model, administration of glial cell line-derived neurotrophic factor protected against neural apoptosis by inducing AKT and glycogen synthase kinase 3 beta phosphorylation. Consistently, when selective AKT inhibitors (LY294002 and triciribine) were used, the protective effect of glial cell line-derived neurotrophic factor was abolished (Yue et al., 2017). Noteworthy, in rotenone-induced rat models of PD, α-bisabolol, a dietary bioactive phytochemical has been found to attenuate dopaminergic neurodegeneration also by increasing the BAX/BCL2 protein expression levels and reducing the expression of cleaved CAS-3 and -9 in the striatum (Javed et al., 2020). Likewise, piperlongumine, an alkaloid isolated from the long pepper Piper longum, exerts an anti-apoptotic role by increasing BCL2 phosphorylation, thus stabilizing the BAX/BCL2 heterodimer and consequently inhibiting apoptosis (Liu et al., 2018). Like in PD, in AD the Aβ oligomers and tau inclusions have been considered to have a pivotal role in the pathogenesis of the disease, leading to neuronal loss, the major cause of neurodegeneration (DeTure and Dickson, 2019). Mitochondrial accumulation of Aβ and tau likely contributes to mitochondrial dysfunction in AD, and it is strictly connected to the mitochondrial apoptosis pathway (Figure 3). Indeed, AD patients’ brains are characterized by excessive oxidative stress, which is sufficient to activate MAPK family members, in particular p38 kinase. Once activated, p38 kinase induces BAX phosphorylation and its translocation to mitochondria where promotes the apoptotic process (Henderson et al., 2017).

F3
Figure 3:
Schematic representation of the involvement of apoptosis in neurological disorders.Neurological disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and epilepsy are characterized by a common feature the apoptosis. In all these diseases, intrinsic apoptosis ultimately leads to cell death by the release of mitochondrial content to the cytoplasm involving BAK/BAX and mitochondrial permeability transition pore (mPTP). These events promote the release of Cytochrome c and the formation of apoptosome inducing the activation of cell death effectors like Caspase-3. Events leading to cell death vary among the different pathologies. In AD, the apoptotic pathway is linked to the mitochondrial accumulation of Aβ-oligomers and tau inclusions which leads to mitochondrial dysfunction allowing the activation of the cell death pathway. In PD, the increase of oxidative stress induces the formation of α-synuclein (α-syn) radical promoting the release of cytochrome C and triggering mitochondria-mediated apoptosis. In MS, activated immune cells, through the release of inflammatory products, promote the activation of caspase-8 which in turn promotes the truncation of BID into t-BID. t-BID represents the point of connection between extrinsic and intrinsic pathways promoting BAK/BAX pore formation and ultimately Caspase-3 activation. In epilepsy, the apoptotic pathway is induced by the excessive stimulation of glutamate receptors. This event results in mitochondrial Ca2+-overload and ultimately apoptotic neuronal cell death. The involvement of apoptosis in neurological disorders is widely described in the main text. Aβ: Amyloid-beta; BAK: B-cell lymphoma 2 (BCL2)-like protein 4; BAX: B-cell lymphoma 2 (BCL2) associated X, apoptosis regulator; BCL2: B-cell lymphoma 2; Ca2+: calcium; FAS: fas cell surface death receptor; FAS-L: ligand of fas cell surface death receptor; MCU: mitochondrial Ca2+ uniporter; mPTP: mitochondrial permeability transition pore; tBID: truncated BH3-interacting domain death agonist; TOM: translocons of the outer membrane; α-syn: alpha-synuclein. Created with BioRender.com.

Furthermore, the intrinsic apoptotic pathway activation has been reported to play the main role in Aβ-42-induced apoptosis (Islam et al., 2017). In this case, Aβ-42 enters the cells by forming a channel-like structure on the cell surface. Here, it provokes mitochondrial damage with consequent cyt-c release and activation of the apoptotic process. Interestingly, Aβ-42 was not able to induce apoptotic cells throughout the activation of the death-inducing signaling complex. It is well established that CAS-3 functionally links Aβ deposition and neurofibrillary tangles in AD. Particularly, both the extracellular Aβ deposits and the intracellular Aβ have been reported to activate caspases, and tau protein CAS-3-mediated cleavage has been reported to play an important role in both tau aggregation and disease (Glabe, 2001; Gamblin et al., 2003). The cognitive decline has been also correlated with increased levels of caspase activity and tau truncated by CAS-3 in the forebrain of aged mice. In addition, in vitro experiments in human neuroblastoma cells demonstrated that the tau cleavage is dependent on CAS-3 (Means et al., 2016). Coherently, the inhibition of caspases prevented the proteolytic cleavage of tau and the associated formation of neurofibrillary tangles involving the apoptosis pathway in both AD neuronal cell death and cognitive impairment (Means et al., 2016). Besides, the role in bioenergetics control and ROS production, mitochondria are important players in intracellular Ca2+ homeostasis (Marchi et al., 2018). Excessive Ca2+-uptake into mitochondria leads to the mitochondrial Ca2+-overload resulting in the opening of mitochondrial permeability transition pore with induction of the apoptosis (Bonora et al., 2017) and neuronal death (Kalani et al., 2018). In vitro studies reported that Aβ oligomers induce Ca2+ transfer to mitochondria from ER and cytosol (Calvo-Rodriguez et al., 2016). In line with the in vitro experiments, it has been reported that increased mitochondrial Ca2+ levels were associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Consistently, Ru360 a selective blocker of mitochondrial Ca2+ uniporter reduced the neuronal Aβ-accumulation, indicating that mitochondrial Ca2+uniporter is required for Aβ-driven mitochondrial Ca2+-uptake (Calvo-Rodriguez et al., 2020). Very recently, it has been also reported an important role of both exogenous and endogenous tau in intracellular Ca2+ homeostasis. Particularly, tau inhibits mitochondrial Ca2+ efflux by blocking the activity of the mitochondrial Na+/Ca2+ exchanger in primary cortical co-cultures of neurons and astrocytes. This provokes depolarization of mitochondria and makes neurons vulnerable to Ca2+-overload-induced apoptotic cell death (Britti et al., 2020). Interestingly, similar events were also found in human iPSC-derived neurons bearing a mutation in the gene encoding tau, the microtubule-associated protein tau (Britti et al., 2020). MS is a debilitating disease characterized by inflammation, loss of myelin sheath that causes axonal degeneration, which makes axons vulnerable to a variety of insults and where the oligodendrocytes are the main targets (Lublin et al., 2014; Patergnani et al., 2017) (Ghasemi et al., 2017). The apoptosis of oligodendrocytes has a critical role in the pathogenesis of MS; indeed, caspase-mediated death of oligodendrocytes is crucial for demyelination (Caprariello et al., 2012). One of the principal apoptotic pathways involved in the regulation of immune response is the fas cell surface death receptor (FAS)/FAS ligand system (Volpe et al., 2016). This pathway leads to the activation of CAS-8, which truncates the BH3 (BCL2 homology 3)-only protein BID (BH3-interacting domain death agonist) into truncated (t)BID (Figure 3). Following the translocation of tBID to mitochondria, this proapoptotic protein induces oligomerization of BAK, thus promoting cyt-c release and mitochondrial apoptotic pathway (Korsmeyer et al., 2000). Recently, it has been found that GSTA4 restricts apoptosis of oligodendrocytes via modulation of the mitochondria-associated FAS-CAS-8-BID-axis. Importantly, it has been reported that GSTA4 can promote remyelination and improve clinical symptoms of MS-like disease in rodents, opening a new perspective for future reparative MS therapies (Carlstrom et al., 2020). Further, it has been demonstrated that another way to control brain apoptosis is through metformin administration. Indeed, metformin reduces the motor impairment in the CPZ-demyelinating mouse model, improves the amounts of myelinating oligodendrocyte and the ADP/ATP ratio, by regulating the AMPK/MTOR pathway. Furthermore, metformin reduces oxidative stress and improves antioxidant defense. This results in a downregulation of the mitochondrial cascade of apoptosis, as demonstrated by a decreased BAX/BCL2 ratio and CAS-3 activation (Sanadgol et al., 2020). Again, matrine, a tetracyclic quinolizine alkaloid derived from the herb radix sophorae flavescentis, has been shown to ameliorate clinical signs in the MS animal models reducing the expression of CAS-3 and cyt-c (Wang et al., 2019b). Thus, targeting the apoptotic process might serve as a therapeutic strategy for improving MS therapy.

Epilepsy is another neurological disorder, which stands out for apoptosis-induced cell death. Seizure episodes are the main features of this neurological disorder characterized by transient and recurrent symptoms due to abnormal and simultaneous neuronal activity of a neuronal cell population in the brain (Brodie et al., 2018). The excessive stimulation of glutamate receptors results in neurotoxicity, leading to mitochondrial Ca2+-overload, in a process denominated excitotoxicity, which leads ultimately to apoptotic neuronal cell death (Figure 3) (Henshall, 2007). Several studies emphasize the role of apoptosis in seizures-induced cell death increased levels of apoptotic markers were observed in epileptic patients. In this group, it was observed augmented levels of CAS-3 and a direct correlation with pro-inflammatory elements, such as IL-1β, IL-6, and CAS-1 (Kegler et al., 2020). In a rat model of kainic acid (KA) induced-epilepsy, after 48 hours of epileptic seizure onset, the number of apoptotic cells in the neocortex increased (Li et al., 2018a). It has been demonstrated that KA-induced epilepsy determines the release of APAF1 into the cytosol to activate the apoptotic cascade via CAS-9 (Henshall, 2007). Furthermore, in the same model, an important role was also accounted for BAD and BAX. Following seizure-induced brain injury, BAD displaces the existing interaction between the anti-apoptotic protein BCL-XL and the pro-apoptotic BAX, which the last one translocates to the mitochondria to promote cyt-c release and activation of the apoptotic cascade (Henshall et al., 2001, 2002). In line with this, sodium valproate treatment significantly reduced neuronal apoptosis, in a KA-induced rat model, by reducing CAS-3 activity and BAX expression and increasing BCL2 levels (Li et al., 2018b). Valepotriate, isolated from Valeriana jatamansi, revealed anti-epileptic effects, in addition to increasing the expression of GABAA, allowing to increased BCL2 and reduced CAS-3 expression levels (Wu et al., 2017). Similarly, vitamin D exhibited neuroprotective effects in hippocampal neurons by reducing BAX and CAS-3 levels in KA- and pentylenetetrazol-induced seizures in rats (Sahin et al., 2019).

Conclusions

Disruption of mitochondrial homeostasis and subsequent mitochondrial dysfunction plays a key role in the pathophysiology of ND. Numerous quality control mechanisms coexist within mitochondria of neural cells to detect and repair defects affecting mitochondrial status and functioning before the point of inescapable cell death is reached. Despite distinct clinical and pathological features, all ND are characterized by alterations of most of these lines of defense and present common harmful cellular events, in particular (i) presence of misfolded and/or aggregated proteins; (ii) anomalies in mitochondrial dynamics; (iii) impairment of autophagy; (iv) mitochondria-driven neuroinflammation; and (v) aberrant apoptosis. Targeting these mitochondria-related processes remains in part complicated, they could be used as a therapeutic target but more needs to be done. To date, we still do not completely understand the exact contribution of the mitochondrial compartment during the forming of misfolded protein aggregates: do they represent the cause or the consequence of these uncontrolled accumulations? Similarly, mitochondrial abnormalities are widely described in the brains of ND-affected persons. However, it is difficult to obtain live monitoring of the mitochondrial dynamics during the progression of the disease.

Several compounds have been described to improve or reduce their activity, but they possess a wide spectrum of side effects. Finally, UPRmt and mito-inflammation represent a relative “young-discovered” mechanism that must be explored in all its facets in the ND context. Further elucidations of ND molecular mechanism, advances in technologies for rapid and constant monitoring of the mitochondrial impairment, major progresses in translating findings from cellular and animal models to humans, and development of specific compounds able to deactivate the mitochondrial imbalances will be a fundamental support to improve the quality of life of people affected by ND.

Author contributions:All authors contributed substantially to discussions of the content. All authors contributed to writing the article and to reviewing and/or editing the manuscript before submission, and approved the final version of the manuscript.

Conflicts of interest:All authors declare no conflicts of interest.

Availability of data and materials:All data generated or analyzed during this study are included in this published article and its supplementary information files.

Open peer reviewer:Karl E Carlström, Karolinska Institutet, Sweden.

Additional file:Open peer review report 1.

F4

P-Reviewer: Carlström KE; C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

Acknowledgments:

We are grateful to Camilla degli Scrovegni for continuous technical support.

References

1. Abrams AJ, Hufnagel RB, Rebelo A, Zanna C, Patel N, Gonzalez MA, Campeanu IJ, Griffin LB, Groenewald S, Strickland AV, Tao F, Speziani F, Abreu L, Schüle R, Caporali L, La Morgia C, Maresca A, Liguori R, Lodi R, Ahmed ZM, et al. 2015 Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder Nat Genet 47 926 932
2. Adamczak S, Dale G, de Rivero Vaccari P, Bullock MR, Dietrich WD, Keane RW 2012 Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome:clinical article J Neurosurg 117 1119 1125
3. Akatsuka H, Kuga S, Masuhara K, Davaadorj O, Okada C, Iida Y, Okada Y, Fukunishi N, Suzuki T, Hosomichi K, Ohtsuka M, Tanaka M, Inoue I, Kimura M, Sato T 2017 AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming through an ATG7-independent pathway Biochem Biophys Res Commun 491 1098 1104
4. Aldridge JE, Horibe T, Hoogenraad NJ 2007 Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements PLoS One 2 e874
5. Alin P, Danielson UH, Mannervik B 1985 4-Hydroxyalk-2-enals are substrates for glutathione transferase FEBS Lett 179 267 270
6. Alirezaei M, Fox HS, Flynn CT, Moore CS, Hebb AL, Frausto RF, Bhan V, Kiosses WB, Whitton JL, Robertson GS, Crocker SJ 2009 Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis Autophagy 5 152 158
7. Ambrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Di Palma M, Marinelli R, Betti M, Minelli A, Cuppini R, Galli F 2019 Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration:the role of vitamin E Biochim Biophys Acta Mol Basis Dis 1865 1098 1112
8. Anderson CJ, Kahl A, Fruitman H, Qian L, Zhou P, Manfredi G, Iadecola C 2020 Prohibitin levels regulate OMA1 activity and turnover in neurons Cell Death Differ 27 1896 1906
9. Anderson CJ, Bredvik K, Burstein SR, Davis C, Meadows SM, Dash J, Case L, Milner TA, Kawamata H, Zuberi A, Piersigilli A, Lutz C, Manfredi G 2019 ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response Acta Neuropathol 138 103 121
10. Angelova PR, Abramov AY 2018 Role of mitochondrial ROS in the brain:from physiology to neurodegeneration FEBS Lett 592 692 702
11. Bader V, Winklhofer KF 2020 Mitochondria at the interface between neurodegeneration and neuroinflammation Semin Cell Dev Biol 99 163 171
12. Baker MR, Fisher KM, Whittaker RG, Griffiths PG, Yu-Wai-Man P, Chinnery PF 2011 Subclinical multisystem neurologic disease in “pure”OPA1 autosomal dominant optic atrophy Neurology 77 1309 1312
13. Becher J, Simula L, Volpe E, Procaccini C, La Rocca C, D'Acunzo P, Cianfanelli V, Strappazzon F, Caruana I, Nazio F, Weber G, Gigantino V, Botti G, Ciccosanti F, Borsellino G, Campello S, Mandolesi G, De Bardi M, Fimia GM, D'Amelio M, et al. 2018 AMBRA1 controls regulatory T-cell differentiation and homeostasis upstream of the FOXO3-FOXP3 axis Dev Cell 47 592 607
14. Beck JS, Mufson EJ, Counts SE 2016 Evidence for mitochondrial UPR gene activation in familial and sporadic Alzheimer's disease Curr Alzheimer Res 13 610 614
15. Beckman JS, Estevez AG, Crow JP, Barbeito L 2001 Superoxide dismutase and the death of motoneurons in ALS Trends Neurosci 24 S15 20
16. Bertani I, Iori V, Trusel M, Maroso M, Foray C, Mantovani S, Tonini R, Vezzani A, Chiesa R 2017 Inhibition of IL-1beta signaling normalizes NMDA-dependent neurotransmission and reduces seizure susceptibility in a mouse model of Creutzfeldt-Jakob disease J Neurosci 37 10278 10289
17. Biasutto L, Azzolini M, Szabo I, Zoratti M 2016 The mitochondrial permeability transition pore in AD 2016:an update Biochim Biophys Acta 1863 2515 2530
18. Bonora M, Bravo-San Pedro JM, Kroemer G, Galluzzi L, Pinton P 2014a Novel insights into the mitochondrial permeability transition Cell Cycle 13 2666 2670
19. Bonora M, De Marchi E, Patergnani S, Suski JM, Celsi F, Bononi A, Giorgi C, Marchi S, Rimessi A, Duszynski J, Pozzan T, Wieckowski MR, Pinton P 2014b Tumor necrosis factor-alpha impairs oligodendroglial differentiation through a mitochondria-dependent process Cell Death Differ 21 1198 1208
20. Bonora M, Morganti C, Morciano G, Pedriali G, Lebiedzinska-Arciszewska M, Aquila G, Giorgi C, Rizzo P, Campo G, Ferrari R, Kroemer G, Wieckowski MR, Galluzzi L, Pinton P 2017 Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation EMBO Rep 18 1077 1089
21. Britti E, Ros J, Esteras N, Abramov AY 2020 Tau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calcium-induced cell death Cell Calcium 86 102150
22. Brodie MJ, Zuberi SM, Scheffer IE, Fisher RS 2018 The 2017 ILAE classification of seizure types and the epilepsies:what do people with epilepsy and their caregivers need to know? Epileptic Disord 20 77 87
23. Calvo-Rodriguez M, Garcia-Durillo M, Villalobos C, Nunez L 2016 Aging enables Ca2+overload and apoptosis induced by amyloid-beta oligomers in rat hippocampal neurons:neuroprotection by non-steroidal anti-inflammatory drugs and R-Flurbiprofen in aging neurons J Alzheimers Dis 54 207 221
24. Calvo-Rodriguez M, Hou SS, Snyder AC, Kharitonova EK, Russ AN, Das S, Fan Z, Muzikansky A, Garcia-Alloza M, Serrano-Pozo A, Hudry E, Bacskai BJ 2020 Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease Nat Commun 11 2146
25. Caprariello AV, Mangla S, Miller RH, Selkirk SM 2012 Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination Ann Neurol 72 395 405
26. Carlstrom KE, Zhu K, Ewing E, Krabbendam IE, Harris RA, Falcao AM, Jagodic M, Castelo-Branco G, Piehl F 2020 Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis Nat Commun 11 4071
27. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD 2005 Mitochondrial Abeta:a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease FASEB J 19 2040 2041
28. Castellazzi M, Patergnani S, Donadio M, Giorgi C, Bonora M, Fainardi E, Casetta I, Granieri E, Pugliatti M, Pinton P 2019a Correlation between auto/mitophagic processes and magnetic resonance imaging activity in multiple sclerosis patients J Neuroinflammation 16 131
29. Castellazzi M, Patergnani S, Donadio M, Giorgi C, Bonora M, Bosi C, Brombo G, Pugliatti M, Seripa D, Zuliani G, Pinton P 2019b Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment Sci Rep 9 20009
30. Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P 1998 Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development Cell 94 727 737
31. Chao de la Barca JM, Simard G, Sarzi E, Chaumette T, Rousseau G, Chupin S, Gadras C, Tessier L, Ferré M, Chevrollier A, Desquiret-Dumas V, Gueguen N, Leruez S, Verny C, Miléa D, Bonneau D, Amati-Bonneau P, Procaccio V, Hamel C, Lenaers G, et al. 2017 Targeted metabolomics reveals early dominant optic atrophy signature in optic nerves of Opa1delTTAG/+mice Invest Ophthalmol Vis Sci 58 812 820
32. Chen H, McCaffery JM, Chan DC 2007 Mitochondrial fusion protects against neurodegeneration in the cerebellum Cell 130 548 562
33. Chen L, Na R, Boldt E, Ran Q 2015 NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure Neurobiol Aging 36 2533 2543
34. Chen L, Cao SQ, Lin ZM, He SJ, Zuo JP 2021 NOD-like receptors in autoimmune diseases Acta Pharmacol Sin 42 1742 1756
35. Chen X, Guo C, Kong J 2012 Oxidative stress in neurodegenerative diseases Neural Regen Res 7 376 385
36. Chen Y, Dorn GW 2nd 2013 PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria Science 340 471 475
37. Chicco AJ, Sparagna GC 2007 Role of cardiolipin alterations in mitochondrial dysfunction and disease Am J Physiol Cell Physiol 292 C33 44
38. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Wang KZQ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, et al. 2013 Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells Nat Cell Biol 15 1197 1205
39. Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L 2004 OPA1 requires mitofusin 1 to promote mitochondrial fusion Proc Natl Acad Sci U S A 101 15927 15932
40. Clausen F, Hanell A, Bjork M, Hillered L, Mir AK, Gram H, Marklund N 2009 Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice Eur J Neurosci 30 385 396
41. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, et al. 2015 A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases Nat Med 21 248 255
42. Cooper JF, Machiela E, Dues DJ, Spielbauer KK, Senchuk MM, Van Raamsdonk JM 2017 Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models Sci Rep 7 16441
43. Corsetti V, Florenzano F, Atlante A, Bobba A, Ciotti MT, Natale F, Della Valle F, Borreca A, Manca A, Meli G, Ferraina C, Feligioni M, D'Aguanno S, Bussani R, Ammassari-Teule M, Nicolin V, Calissano P, Amadoro G 2015 NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1:implications in Alzheimer's disease Hum Mol Genet 24 3058 3081
44. Cummins N, Tweedie A, Zuryn S, Bertran-Gonzalez J, Gotz J 2019 Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria EMBO J 38 e99360
45. Danese A, Leo S, Rimessi A, Wieckowski MR, Fiorica F, Giorgi C, Pinton P 2021 Cell death as a result of calcium signaling modulation:a cancer-centric prospective Biochim Biophys Acta Mol Cell Res 1868 119061
46. de Castro IP, Martins LM, Loh SH 2011 Mitochondrial quality control and Parkinson's disease:a pathway unfolds Mol Neurobiol 43 80 86
47. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW 2008 A molecular platform in neurons regulates inflammation after spinal cord injury J Neurosci 28 3404 3414
48. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP 2000 Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy Nat Genet 26 207 210
49. Dempsey C, Rubio Araiz A, Bryson KJ, Finucane O, Larkin C, Mills EL, Robertson AAB, Cooper MA, O'Neill LAJ, Lynch MA 2017 Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice Brain Behav Immun 61 306 316
50. Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AAB, Atkin JD, Cooper MA, Schroder K, Yerbury JJ, Gordon R, Woodruff TM 2020 The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins Glia 68 407 421
51. Deter RL, Baudhuin P, De Duve C 1967 Participation of lysosomes in cellular autophagy induced in rat liver by glucagon J Cell Biol 35 C11 16
52. DeTure MA, Dickson DW 2019 The neuropathological diagnosis of Alzheimer's disease Mol Neurodegener 14 32
53. Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK 2008 Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain J Biol Chem 283 9089 9100
54. Di Maio R, Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT 2016 alpha-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease Sci Transl Med 8 342ra78
55. Doxaki C, Palikaras K 2020 Neuronal mitophagy:friend or foe? Front Cell Dev Biol 8 611938
56. Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG, Wu L, Yan SF, Tieu K, Yan SS 2017 PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease Brain 140 3233 3251
57. Eitas TK, Chou WC, Wen H, Gris D, Robbins GR, Brickey J, Oyama Y, Ting JP 2014 The nucleotide-binding leucine-rich repeat (NLR) family member NLRX1 mediates protection against experimental autoimmune encephalomyelitis and represses macrophage/microglia-induced inflammation J Biol Chem 289 4173 4179
58. Fan Z, Pan YT, Zhang ZY, Yang H, Yu SY, Zheng Y, Ma JH, Wang XM 2020 Systemic activation of NLRP3 inflammasome and plasma alpha-synuclein levels are correlated with motor severity and progression in Parkinson's disease J Neuroinflammation 17 11
59. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktaschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA 2019 Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease Nat Neurosci 22 401 412
60. Fessler E, Eckl EM, Schmitt S, Mancilla IA, Meyer-Bender MF, Hanf M, Philippou-Massier J, Krebs S, Zischka H, Jae LT 2020 A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol Nature 579 433 437
61. Fiorese CJ, Schulz AM, Lin YF, Rosin N, Pellegrino MW, Haynes CM 2016 The transcription factor ATF5 mediates a mammalian mitochondrial UPR Curr Biol 26 2037 2043
62. Flippo KH, Strack S 2017 Mitochondrial dynamics in neuronal injury, development and plasticity J Cell Sci 130 671 681
63. Flores J, Noel A, Foveau B, Lynham J, Lecrux C, LeBlanc AC 2018 Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model Nat Commun 9 3916
64. Franco-Iborra S, Vila M, Perier C 2018 Mitochondrial quality control in neurodegenerative diseases:focus on Parkinson's disease and Huntington's disease Front Neurosci 12 342
65. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ 2001 The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis Dev Cell 1 515 525
66. Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP 2017 NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes J Exp Med 214 1351 1370
67. Galluzzi L, Bravo-San Pedro JM, Kepp O, Kroemer G 2016 Regulated cell death and adaptive stress responses Cell Mol Life Sci 73 2405 2410
68. Galluzzi L, Maiuri MC, Vitale I, Zischka H, Castedo M, Zitvogel L, Kroemer G 2007 Cell death modalities:classification and pathophysiological implications Cell Death Differ 14 1237 1243
69. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, et al. 2018 Molecular mechanisms of cell death:recommendations of the Nomenclature Committee on Cell Death 2018 Cell Death Differ 25 486 541
70. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL 2003 Caspase cleavage of tau:linking amyloid and neurofibrillary tangles in Alzheimer's disease Proc Natl Acad Sci U S A 100 10032 10037
71. Garcia-Sierra F, Mondragon-Rodriguez S, Basurto-Islas G 2008 Truncation of tau protein and its pathological significance in Alzheimer's disease J Alzheimers Dis 14 401 409
72. Garcia I, Crowther AJ, Gama V, Miller CR, Deshmukh M, Gershon TR 2015 Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation Oncogene 34 3881
73. Gautier CA, Erpapazoglou Z, Mouton-Liger F, Muriel MP, Cormier F, Bigou S, Duffaure S, Girard M, Foret B, Iannielli A, Broccoli V, Dalle C, Bohl D, Michel PP, Corvol JC, Brice A, Corti O 2016 The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations Hum Mol Genet 25 2972 2984
74. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W 2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 Nat Cell Biol 12 119 131
75. Ghasemi N, Razavi S, Nikzad E 2017 Multiple sclerosis:pathogenesis, symptoms, diagnoses and cell-based therapy Cell J 19 1 10
76. Ghio S, Kamp F, Cauchi R, Giese A, Vassallo N 2016 Interaction of alpha-synuclein with biomembranes in Parkinson's disease--role of cardiolipin Prog Lipid Res 61 73 82
77. Giorgi C, Danese A, Missiroli S, Patergnani S, Pinton P 2018 Calcium dynamics as a machine for decoding signals Trends Cell Biol 28 258 273
78. Giorgi C, Baldassari F, Bononi A, Bonora M, De Marchi E, Marchi S, Missiroli S, Patergnani S, Rimessi A, Suski JM, Wieckowski MR, Pinton P 2012 Mitochondrial Ca(2+) and apoptosis Cell Calcium 52 36 43
79. Girard M, Lariviere R, Parfitt DA, Deane EC, Gaudet R, Nossova N, Blondeau F, Prenosil G, Vermeulen EG, Duchen MR, Richter A, Shoubridge EA, Gehring K, McKinney RA, Brais B, Chapple JP, McPherson PS 2012 Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) Proc Natl Acad Sci U S A 109 1661 1666
80. Glabe C 2001 Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease J Mol Neurosci 17 137 145
81. Gomez M, Germain D 2019 Cross talk between SOD1 and the mitochondrial UPR in cancer and neurodegeneration Mol Cell Neurosci 98 12 18
82. Gong Z, Pan J, Shen Q, Li M, Peng Y 2018 Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury J Neuroinflammation 15 242
83. Gorlach A, Bertram K, Hudecova S, Krizanova O 2015 Calcium and ROS:a mutual interplay Redox Biol 6 260 271
84. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C 1989 Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease Proc Natl Acad Sci U S A 86 7611 7615
85. Gugliandolo A, Giacoppo S, Bramanti P, Mazzon E 2018 NLRP3 inflammasome activation in a transgenic amyotrophic lateral sclerosis model Inflammation 41 93 103
86. Guillery O, Malka F, Landes T, Guillou E, Blackstone C, Lombes A, Belenguer P, Arnoult D, Rojo M 2008 Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential Biol Cell 100 315 325
87. Guo X, Aviles G, Liu Y, Tian R, Unger BA, Lin YT, Wiita AP, Xu K, Correia MA, Kampmann M 2020 Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway Nature 579 427 432
88. Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C 2015 NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes PLoS One 10 e0130624
89. Gustot A, Gallea JI, Sarroukh R, Celej MS, Ruysschaert JM, Raussens V 2015 Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease Biochem J 471 323 333
90. Haas RH, Nasirian F, Nakano K, Ward D, Pay M, Hill R, Shults CW 1995 Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson's disease Ann Neurol 37 714 722
91. Han Q, Xu XM 2021 Mitochondrial integrity in neuronal injury and repair Neural Regen Res 16 674 675
92. Harbauer AB, Zahedi RP, Sickmann A, Pfanner N, Meisinger C 2014 The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease Cell Metab 19 357 372
93. Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y, Hirsch EC 2000 Caspase-3:A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease Proc Natl Acad Sci U S A 97 2875 2880
94. Hassanpour M, Cheraghi O, Laghusi D, Nouri M, Panahi Y 2020 The relationship between ANT1 and NFL with autophagy and mitophagy markers in patients with multiple sclerosis J Clin Neurosci 78 307 312
95. Haynes CM, Ron D 2010 The mitochondrial UPR - protecting organelle protein homeostasis J Cell Sci 123 3849 3855
96. Henderson LE, Abdelmegeed MA, Yoo SH, Rhee SG, Zhu X, Smith MA, Nguyen RQ, Perry G, Song BJ 2017 Enhanced phosphorylation of Bax and its translocation into mitochondria in the brains of individuals affiliated with Alzheimer's disease Open Neurol J 11 48 58
97. Heneka MT, McManus RM, Latz E 2018 Inflammasome signalling in brain function and neurodegenerative disease Nat Rev Neurosci 19 610 621
98. Henshall DC 2007 Apoptosis signalling pathways in seizure-induced neuronal death and epilepsy Biochem Soc Trans 35 421 423
99. Henshall DC, Araki T, Schindler CK, Lan JQ, Tiekoter KL, Taki W, Simon RP 2002 Activation of Bcl-2-associated death protein and counter-response of Akt within cell populations during seizure-induced neuronal death J Neurosci 22 8458 8465
100. Henshall DC, Bonislawski DP, Skradski SL, Araki T, Lan JQ, Schindler CK, Meller R, Simon RP 2001 Formation of the Apaf-1/cytochrome c complex precedes activation of caspase-9 during seizure-induced neuronal death Cell Death Differ 8 1169 1181
101. Hernandez IH, Torres-Peraza J, Santos-Galindo M, Ramos-Moron E, Fernandez-Fernandez MR, Perez-Alvarez MJ, Miranda-Vizuete A, Lucas JJ 2017 The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington's disease Acta Neuropathol 134 839 850
102. Holbrook JA, Jarosz-Griffiths HH, Caseley E, Lara-Reyna S, Poulter JA, Williams-Gray CH, Peckham D, McDermott MF 2021 Neurodegenerative disease and the NLRP3 inflammasome Front Pharmacol 12 643254
103. Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J 2013 Mitonuclear protein imbalance as a conserved longevity mechanism Nature 497 451 457
104. Hu D, Sun X, Liao X, Zhang X, Zarabi S, Schimmer A, Hong Y, Ford C, Luo Y, Qi X 2019 Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity Acta Neuropathol 137 939 960
105. Hunot S, Dugas N, Faucheux B, Hartmann A, Tardieu M, Debre P, Agid Y, Dugas B, Hirsch EC 1999 FcepsilonRII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells J Neurosci 19 3440 3447
106. Igoudjil A, Magrane J, Fischer LR, Kim HJ, Hervias I, Dumont M, Cortez C, Glass JD, Starkov AA, Manfredi G 2011 In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space J Neurosci 31 15826 15837
107. Imbeault E, Mahvelati TM, Braun R, Gris P, Gris D 2014 Nlrx1 regulates neuronal cell death Mol Brain 7 90
108. Ineichen BV, Zhu K, Carlstrom KE 2021 Axonal mitochondria adjust in size depending on g-ratio of surrounding myelin during homeostasis and advanced remyelination J Neurosci Res 99 793 805
109. Inoue M, Shinohara ML 2013 NLRP3 inflammasome and MS/EAE Autoimmune Dis 2013 859145
110. Ishihara N, Fujita Y, Oka T, Mihara K 2006 Regulation of mitochondrial morphology through proteolytic cleavage of OPA1 EMBO J 25 2966 2977
111. Islam MI, Sharoar MG, Ryu EK, Park IS 2017 Limited activation of the intrinsic apoptotic pathway plays a main role in amyloid-beta-induced apoptosis without eliciting the activation of the extrinsic apoptotic pathway Int J Mol Med 40 1971 1982
112. Ismael S, Zhao L, Nasoohi S, Ishrat T 2018 Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke Sci Rep 8 5971
113. Israelson A, Arbel N, Da Cruz S, Ilieva H, Yamanaka K, Shoshan-Barmatz V, Cleveland DW 2010 Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS Neuron 67 575 587
114. Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL, Sutterwala FS 2013 Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation Immunity 39 311 323
115. Javed H, Meeran MFN, Azimullah S, Bader Eddin L, Dwivedi VD, Jha NK, Ojha S 2020 alpha-Bisabolol, a dietary bioactive phytochemical attenuates dopaminergic neurodegeneration through modulation of oxidative stress, neuroinflammation and apoptosis in rotenone-induced rat model of Parkinson's disease Biomolecules 10 1421
116. Jha NK, Jha SK, Kar R, Nand P, Swati K, Goswami VK 2019 Nuclear factor-kappa beta as a therapeutic target for Alzheimer's disease J Neurochem 150 113 137
117. Jin MF, Ni H, Li LL 2018 Leptin maintained Zinc homeostasis against glutamate-induced excitotoxicity by preventing mitophagy-mediated mitochondrial activation in HT22 hippocampal neuronal cells Front Neurol 9 322
118. Johann S, Heitzer M, Kanagaratnam M, Goswami A, Rizo T, Weis J, Troost D, Beyer C 2015 NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients Glia 63 2260 2273
119. Joodi Khanghah O, Nourazarian A, Khaki-Khatibi F, Nikanfar M, Laghousi D, Vatankhah AM, Moharami S 2020 Evaluation of the diagnostic and predictive value of serum levels of ANT1, ATG5, and Parkin in multiple sclerosis Clin Neurol Neurosurg 197 106197
120. Joshi AU, Minhas PS, Liddelow SA, Haileselassie B, Andreasson KI, Dorn GW, 2nd, Mochly-Rosen D 2019 Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration Nat Neurosci 22 1635 1648
121. Joubert PE, Meiffren G, Gregoire IP, Pontini G, Richetta C, Flacher M, Azocar O, Vidalain PO, Vidal M, Lotteau V, Codogno P, Rabourdin-Combe C, Faure M 2009 Autophagy induction by the pathogen receptor CD46 Cell Host Microbe 6 354 366
122. Julienne H, Buhl E, Leslie DS, Hodge JJL 2017 Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes Neurobiol Dis 104 15 23
123. Kalani K, Yan SF, Yan SS 2018 Mitochondrial permeability transition pore:a potential drug target for neurodegeneration Drug Discov Today 23 1983 1989
124. Kaltschmidt B, Kaltschmidt C 2015 NF-KappaB in long-term memory and structural plasticity in the adult mammalian brain Front Mol Neurosci 8 69
125. Kasashima K, Sumitani M, Satoh M, Endo H 2008 Human prohibitin 1 maintains the organization and stability of the mitochondrial nucleoids Exp Cell Res 314 988 996
126. Kaushal V, Dye R, Pakavathkumar P, Foveau B, Flores J, Hyman B, Ghetti B, Koller BH, LeBlanc AC 2015 Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation Cell Death Differ 22 1676 1686
127. Kawamata H, Manfredi G 2010 Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space Antioxid Redox Signal 13 1375 1384
128. Kawamoto Y, Ito H, Ayaki T, Takahashi R 2014 Immunohistochemical localization of apoptosome-related proteins in Lewy bodies in Parkinson's disease and dementia with Lewy bodies Brain Res 1571 39 48
129. Keane RW, Dietrich WD, de Rivero Vaccari JP 2018 Inflammasome proteins as biomarkers of multiple sclerosis Front Neurol 9 135
130. Keeney PM, Xie J, Capaldi RA, Bennett JP Jr 2006 Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled J Neurosci 26 5256 5264
131. Kegler A, Caprara ALF, Pascotini ET, Arend J, Gabbi P, Duarte M, Furian AF, Oliveira MS, Royes LFF, Fighera MR 2020 Apoptotic markers are increased in epilepsy patients:a relation with manganese superoxide dismutase Ala16Val polymorphism and seizure type through IL-1beta and IL-6 pathways Biomed Res Int 2020 6250429
132. Kelm-Nelson CA, Brauer AFL, Barth KJ, Lake JM, Sinnen MLK, Stehula FJ, Muslu C, Marongiu R, Kaplitt MG, Ciucci MR 2018 Characterization of early-onset motor deficits in the Pink1-/- mouse model of Parkinson disease Brain Res 1680 1 12
133. Kenny TC, Germain D 2017 From discovery of the CHOP axis and targeting ClpP to the identification of additional axes of the UPRmt driven by the estrogen receptor and SIRT3 J Bioenerg Biomembr 49 297 305
134. Killackey SA, Rahman MA, Soares F, Zhang AB, Abdel-Nour M, Philpott DJ, Girardin SE 2019 The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1 Mol Cell Biochem 453 187 196
135. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N 1998 Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism Nature 392 605 608
136. Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J 2007 Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice Proc Natl Acad Sci U S A 104 11441 11446
137. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, et al. 2021 Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)(1) Autophagy 17 1 382
138. Koirala S, Guo Q, Kalia R, Bui HT, Eckert DM, Frost A, Shaw JM 2013 Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission Proc Natl Acad Sci U S A 110 E1342 1351
139. Kooistra J, Milojevic J, Melacini G, Ortega J 2009 A new function of human HtrA2 as an amyloid-beta oligomerization inhibitor J Alzheimers Dis 17 281 294
140. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH 2000 Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c Cell Death Differ 7 1166 1173
141. Korwitz A, Merkwirth C, Richter-Dennerlein R, Troder SE, Sprenger HG, Quiros PM, Lopez-Otin C, Rugarli EI, Langer T 2016 Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria J Cell Biol 212 157 166
142. Kumar A, Ganini D, Mason RP 2016 Role of cytochrome c in alpha-synuclein radical formation:implications of alpha-synuclein in neuronal death in Maneb- and paraquat-induced model of Parkinson's disease Mol Neurodegener 11 70
143. Lai M, Yao H, Shah SZA, Wu W, Wang D, Zhao Y, Wang L, Zhou X, Zhao D, Yang L 2018 The NLRP3-Caspase 1 inflammasome negatively regulates autophagy via TLR4-TRIF in prion peptide-infected microglia Front Aging Neurosci 10 116
144. Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, Lee WP, Hoffman HM, Dixit VM 2009 Glyburide inhibits the Cryopyrin/Nalp3 inflammasome J Cell Biol 187 61 70
145. Lampron A, Elali A, Rivest S 2013 Innate immunity in the CNS:redefining the relationship between the CNS and Its environment Neuron 78 214 232
146. Lebeau J, Saunders JM, Moraes VWR, Madhavan A, Madrazo N, Anthony MC, Wiseman RL 2018 The PERK arm of the unfolded protein response regulates mitochondrial morphology during acute endoplasmic reticulum stress Cell Rep 22 2827 2836
147. Lee E, Hwang I, Park S, Hong S, Hwang B, Cho Y, Son J, Yu JW 2019 MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration Cell Death Differ 26 213 228
148. Lezi E, Swerdlow RH 2012 Mitochondria in neurodegeneration Adv Exp Med Biol 942 269 286
149. Li Q, Han Y, Du J, Jin H, Zhang J, Niu M, Qin J 2018a Alterations of apoptosis and autophagy in developing brain of rats with epilepsy:changes in LC3, P62, Beclin-1 and Bcl-2 levels Neurosci Res 130 47 55
150. Li Q, Li QQ, Jia JN, Cao S, Wang ZB, Wang X, Luo C, Zhou HH, Liu ZQ, Mao XY 2018b Sodium valproate ameliorates neuronal apoptosis in a kainic acid model of epilepsy via enhancing PKC-dependent GABAAR gamma2 serine 327 phosphorylation Neurochem Res 43 2343 2352
151. Li Z, Peng Y, Hufnagel RB, Hu YC, Zhao C, Queme LF, Khuchua Z, Driver AM, Dong F, Lu QR, Lindquist DM, Jankowski MP, Stottmann RW, Kao WWY, Huang T 2017 Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice Hum Mol Genet 26 3776 3791
152. Lin MT, Beal MF 2006 Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases Nature 443 787 795
153. Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L, Gao G, Wu X, Wang X, Yang H 2018 Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models Autophagy 14 845 861
154. Liu L, Chan C 2014 IPAF inflammasome is involved in interleukin-1beta production from astrocytes, induced by palmitate;implications for Alzheimer's Disease Neurobiol Aging 35 309 321
155. Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, et al. 2012 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells Nat Cell Biol 14 177 185
156. Longo F, Benedetti S, Zambon AA, Sora MGN, Di Resta C, De Ritis D, Quattrini A, Maltecca F, Ferrari M, Previtali SC 2020 Impaired turnover of hyperfused mitochondria in severe axonal neuropathy due to a novel DRP1 mutation Hum Mol Genet 29 177 188
157. Los M, Mozoluk M, Ferrari D, Stepczynska A, Stroh C, Renz A, Herceg Z, Wang ZQ, Schulze-Osthoff K 2002 Activation and caspase-mediated inhibition of PARP:a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling Mol Biol Cell 13 978 988
158. Losón OC, Song Z, Chen H, Chan DC 2013 Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission Mol Biol Cell 24 659 667
159. Lovell MA, Markesbery WR 2007 Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease Nucleic Acids Res 35 7497 7504
160. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, et al. 2014 Defining the clinical course of multiple sclerosis:the 2013 revisions Neurology 83 278 286
161. Ma C, Pan Y, Yang Z, Meng Z, Sun R, Wang T, Fei Y, Fan W 2016 Pre-administration of BAX-inhibiting peptides decrease the loss of the nigral dopaminergic neurons in rats Life Sci 144 113 120
162. Magrane J, Cortez C, Gan WB, Manfredi G 2014 Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models Hum Mol Genet 23 1413 1424
163. Mai N, Chrzanowska-Lightowlers ZM, Lightowlers RN 2017 The process of mammalian mitochondrial protein synthesis Cell Tissue Res 367 5 20
164. Maier A, Deigendesch N, Muller K, Weishaupt JH, Krannich A, Rohle R, Meissner F, Molawi K, Munch C, Holm T, Meyer R, Meyer T, Zychlinsky A 2015 Interleukin-1 antagonist anakinra in amyotrophic lateral sclerosis--a pilot study PLoS One 10 e0139684
165. Mao Z, Liu C, Ji S, Yang Q, Ye H, Han H, Xue Z 2017 The NLRP3 inflammasome is involved in the pathogenesis of Parkinson's disease in rats Neurochem Res 42 1104 1115
166. Marchi S, Patergnani S, Pinton P 2014 The endoplasmic reticulum-mitochondria connection:one touch, multiple functions Biochim Biophys Acta 1837 461 469
167. Marchi S, Patergnani S, Missiroli S, Morciano G, Rimessi A, Wieckowski MR, Giorgi C, Pinton P 2018 Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death Cell Calcium 69 62 72
168. Martinez BA, Petersen DA, Gaeta AL, Stanley SP, Caldwell GA, Caldwell KA 2017 Dysregulation of the mitochondrial unfolded protein response induces non-apoptotic dopaminergic neurodegeneration in C. elegans models of Parkinson's disease J Neurosci 37 11085 11100
169. Martinus RD, Garth GP, Webster TL, Cartwright P, Naylor DJ, Hoj PB, Hoogenraad NJ 1996 Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome Eur J Biochem 240 98 103
170. Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, Ruggiero EA, Crawford DR 2012 Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration J Alzheimers Dis 30 617 627
171. McCracken E, Valeriani V, Simpson C, Jover T, McCulloch J, Dewar D 2000 The lipid peroxidation by-product 4-hydroxynonenal is toxic to axons and oligodendrocytes J Cereb Blood Flow Metab 20 1529 1536
172. McKenzie BA, Mamik MK, Saito LB, Boghozian R, Monaco MC, Major EO, Lu JQ, Branton WG, Power C 2018 Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis Proc Natl Acad Sci U S A 115 E6065 E6074
173. Means JC, Gerdes BC, Kaja S, Sumien N, Payne AJ, Stark DA, Borden PK, Price JL, Koulen P 2016 Caspase-3-dependent proteolytic cleavage of Tau causes neurofibrillary tangles and results in cognitive impairment during normal aging Neurochem Res 41 2278 2288
174. Mecocci P, MacGarvey U, Beal MF 1994 Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease Ann Neurol 36 747 751
175. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J 2009 A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase Proc Natl Acad Sci U S A 106 11960 11965
176. Moehle EA, Shen K, Dillin A 2019 Mitochondrial proteostasis in the context of cellular and organismal health and aging J Biol Chem 294 5396 5407
177. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T 1994 Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients Neurosci Lett 180 147 150
178. Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T 2000 Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain J Neural Transm (Vienna) 107 335 341
179. Monteiro-Cardoso VF, Oliveira MM, Melo T, Domingues MR, Moreira PI, Ferreiro E, Peixoto F, Videira RA 2015 Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer's disease J Alzheimers Dis 43 1375 1392
180. Morais VA, Haddad D, Craessaerts K, De Bock PJ, Swerts J, Vilain S, Aerts L, Overbergh L, Grunewald A, Seibler P, Klein C, Gevaert K, Verstreken P, De Strooper B 2014 PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling Science 344 203 207
181. Mouton-Liger F, Rosazza T, Sepulveda-Diaz J, Ieang A, Hassoun SM, Claire E, Mangone G, Brice A, Michel PP, Corvol JC, Corti O 2018 Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop Glia 66 1736 1751
182. Murphy MP 2009 How mitochondria produce reactive oxygen species Biochem J 417 1 13
183. Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM 2012 Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation Science 337 587 590
184. Neuspiel M, Schauss AC, Braschi E, Zunino R, Rippstein P, Rachubinski RA, Andrade-Navarro MA, McBride HM 2008 Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers Curr Biol 18 102 108
185. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Lohr F, Popovic D, Occhipinti A, Reichert AS, Terzic J, Dotsch V, Ney PA, Dikic I 2010 Nix is a selective autophagy receptor for mitochondrial clearance EMBO Rep 11 45 51
186. Oettinghaus B, D'Alonzo D, Barbieri E, Restelli LM, Savoia C, Licci M, Tolnay M, Frank S, Scorrano L 2016 DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress Biochim Biophys Acta 1857 1267 1276
187. Okumura M, Saiki M, Yamaguchi H, Hidaka Y 2011 Acceleration of disulfide-coupled protein folding using glutathione derivatives FEBS J 278 1137 1144
188. Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ 2008 N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking J Neurosci 28 2783 2792
189. Panda C, Voelz C, Habib P, Mevissen C, Pufe T, Beyer C, Gupta S, Slowik A 2021 Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 inflammasome expression and autophagy in human microglial cells Cells 10 1652
190. Papa L, Germain D 2011 Estrogen receptor mediates a distinct mitochondrial unfolded protein response J Cell Sci 124 1396 1402
191. Papa L, Germain D 2014 SirT3 regulates the mitochondrial unfolded protein response Mol Cell Biol 34 699 710
192. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P 2008 Mitochondrial association of alpha-synuclein causes oxidative stress Cell Mol Life Sci 65 1272 1284
193. Park HJ, Kim SS, Seong YM, Kim KH, Goo HG, Yoon EJ, Min do S, Kang S, Rhim H 2006 Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria J Biol Chem 281 34277 34287
194. Patergnani S, Vitto VAM, Pinton P, Rimessi A 2020a Mitochondrial stress responses and “mito-inflammation”in cystic fibrosis Front Pharmacol 11 581114
195. Patergnani S, Bouhamida E, Leo S, Pinton P, Rimessi A 2021a Mitochondrial oxidative stress and “mito-inflammation”:actors in the diseases Biomedicines 9 216
196. Patergnani S, Danese A, Bouhamida E, Aguiari G, Previati M, Pinton P, Giorgi C 2020b Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer Int J Mol Sci 21 8323
197. Patergnani S, Fossati V, Bonora M, Giorgi C, Marchi S, Missiroli S, Rusielewicz T, Wieckowski MR, Pinton P 2017 Mitochondria in multiple sclerosis:molecular mechanisms of pathogenesis Int Rev Cell Mol Biol 328 49 103
198. Patergnani S, Castellazzi M, Bonora M, Marchi S, Casetta I, Pugliatti M, Giorgi C, Granieri E, Pinton P 2018 Autophagy and mitophagy elements are increased in body fluids of multiple sclerosis-affected individuals J Neurol Neurosurg Psychiatry 89 439 441
199. Patergnani S, Bonora M, Bouhamida E, Danese A, Marchi S, Morciano G, Previati M, Pedriali G, Rimessi A, Anania G, Giorgi C, Pinton P 2021b Methods to monitor mitophagy and mitochondrial quality:implications in cancer, neurodegeneration, and cardiovascular diseases Methods Mol Biol 2310 113 159
200. Patergnani S, Bonora M, Ingusci S, Previati M, Marchi S, Zucchini S, Perrone M, Wieckowski MR, Castellazzi M, Pugliatti M, Giorgi C, Simonato M, Pinton P 2021c Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis Proc Natl Acad Sci U S A 118 e202007811
201. Paunovic V, Petrovic IV, Milenkovic M, Janjetovic K, Pravica V, Dujmovic I, Milosevic E, Martinovic V, Mesaros S, Drulovic J, Trajkovic V 2018 Autophagy-independent increase of ATG5 expression in T cells of multiple sclerosis patients J Neuroimmunol 319 100 105
202. Pedrini S, Sau D, Guareschi S, Bogush M, Brown RH Jr, Naniche N, Kia A, Trotti D, Pasinelli P 2010 ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2 Hum Mol Genet 19 2974 2986
203. Perez FA, Palmiter RD 2005 Parkin-deficient mice are not a robust model of parkinsonism Proc Natl Acad Sci U S A 102 2174 2179
204. Perez MJ, Ivanyuk D, Panagiotakopoulou V, Di Napoli G, Kalb S, Brunetti D, Al-Shaana R, Kaeser SA, Fraschka SA, Jucker M, Zeviani M, Viscomi C, Deleidi M 2020 Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer's disease-like pathology in human cerebral organoids Mol Psychiatry doi:10.1038/s41380-020-0807-4
205. Pfanner N, Warscheid B, Wiedemann N 2019 Mitochondrial proteins:from biogenesis to functional networks Nat Rev Mol Cell Biol 20 267 284
206. Pharaoh G, Sataranatarajan K, Street K, Hill S, Gregston J, Ahn B, Kinter C, Kinter M, Van Remmen H 2019 Metabolic and stress response changes precede disease onset in the spinal cord of mutant SOD1 ALS mice Front Neurosci 13 487
207. Piccoli C, Sardanelli A, Scrima R, Ripoli M, Quarato G, D'Aprile A, Bellomo F, Scacco S, De Michele G, Filla A, Iuso A, Boffoli D, Capitanio N, Papa S 2008 Mitochondrial respiratory dysfunction in familiar parkinsonism associated with PINK1 mutation Neurochem Res 33 2565 2574
208. Pickles S, Vigie P, Youle RJ 2018 Mitophagy and quality control mechanisms in mitochondrial maintenance Curr Biol 28 R170 185
209. Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP, Hoekstra JG, Harper JW, Youle RJ 2015 Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress Neuron 87 371 381
210. Pimenta de Castro I, Costa AC, Lam D, Tufi R, Fedele V, Moisoi N, Dinsdale D, Deas E, Loh SH, Martins LM 2012 Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster Cell Death Differ 19 1308 1316
211. Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, Alcolea D, Lleo A, Molinuevo JL, Serra N, Trullas R 2013 Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease Ann Neurol 74 655 668
212. Pontillo A, Catamo E, Arosio B, Mari D, Crovella S 2012 NALP1/NLRP1 genetic variants are associated with Alzheimer disease Alzheimer Dis Assoc Disord 26 277 281
213. Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Rudzińska-Bar M, Aasly JO, et al. 2017 Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism Brain 140 98 117
214. Pyakurel A, Savoia C, Hess D, Scorrano L 2015 Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis Mol Cell 58 244 254
215. Pyle A, Brennan R, Kurzawa-Akanbi M, Yarnall A, Thouin A, Mollenhauer B, Burn D, Chinnery PF, Hudson G 2015 Reduced cerebrospinal fluid mitochondrial DNA is a biomarker for early-stage Parkinson's disease Ann Neurol 78 1000 1004
216. Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J 2006 Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis J Biol Chem 281 31950 31962
217. Quintana-Cabrera R, Manjarres-Raza I, Vicente-Gutierrez C, Corrado M, Bolanos JP, Scorrano L 2021 Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria Redox Biol 41 101944
218. Quiros PM, Prado MA, Zamboni N, D'Amico D, Williams RW, Finley D, Gygi SP, Auwerx J 2017 Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals J Cell Biol 216 2027 2045
219. Rahman S 2015 Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus Epilepsy Behav 49 71 75
220. Rainbolt TK, Lebeau J, Puchades C, Wiseman RL 2016 Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteolytic activity during stress Cell Rep 14 2041 2049
221. Rasola A, Bernardi P 2011 Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis Cell Calcium 50 222 233
222. Ren J, Yuan L, Wang W, Zhang M, Wang Q, Li S, Zhang L, Hu K 2019 Tricetin protects against 6-OHDA-induced neurotoxicity in Parkinson's disease model by activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway Toxicol Appl Pharmacol 378 114617
223. Riar AK, Burstein SR, Palomo GM, Arreguin A, Manfredi G, Germain D 2017 Sex specific activation of the ERalpha axis of the mitochondrial UPR (UPRmt) in the G93A-SOD1 mouse model of familial ALS Hum Mol Genet 26 1318 1327
224. Rimessi A, Previati M, Nigro F, Wieckowski MR, Pinton P 2016 Mitochondrial reactive oxygen species and inflammation:Molecular mechanisms, diseases and promising therapies Int J Biochem Cell Biol 81 281 293
225. Rimessi A, Bezzerri V, Patergnani S, Marchi S, Cabrini G, Pinton P 2015 Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis Nat Commun 6 6201
226. Rolland SG, Schneid S, Schwarz M, Rackles E, Fischer C, Haeussler S, Regmi SG, Yeroslaviz A, Habermann B, Mokranjac D, Lambie E, Conradt B 2019 Compromised mitochondrial protein import acts as a signal for UPR(mt) Cell Rep 28 1659 1669
227. Rubartelli A 2014 DAMP-mediated activation of NLRP3-inflammasome in brain sterile inflammation:the fine line between healing and neurodegeneration Front Immunol 5 99
228. Ruggiero FM, Cafagna F, Petruzzella V, Gadaleta MN, Quagliariello E 1992 Lipid composition in synaptic and nonsynaptic mitochondria from rat brains and effect of aging J Neurochem 59 487 491
229. Sahin S, Gurgen SG, Yazar U, Ince I, Kamasak T, Acar Arslan E, Diler Durgut B, Dilber B, Cansu A 2019 Vitamin D protects against hippocampal apoptosis related with seizures induced by kainic acid and pentylenetetrazol in rats Epilepsy Res 149 107 116
230. Sanadgol N, Barati M, Houshmand F, Hassani S, Clarner T, Shahlaei M, Golab F 2020 Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period Pharmacol Rep 72 641 658
231. Santos D, Esteves AR, Silva DF, Januario C, Cardoso SM 2015 The impact of mitochondrial fusion and fission modulation in sporadic Parkinson's disease Mol Neurobiol 52 573 586
232. Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R, Mancuso R, Clerici M 2016 The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease Mol Neurodegener 11 23
233. Sarkar S, Malovic E, Harishchandra DS, Ghaisas S, Panicker N, Charli A, Palanisamy BN, Rokad D, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG 2017 Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease NPJ Parkinsons Dis 3 30
234. Sarzi E, Angebault C, Seveno M, Gueguen N, Chaix B, Bielicki G, Boddaert N, Mausset-Bonnefont AL, Cazevieille C, Rigau V, Renou JP, Wang J, Delettre C, Brabet P, Puel JL, Hamel CP, Reynier P, Lenaers G 2012 The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse Brain 135 3599 3613
235. Schmukler E, Solomon S, Simonovitch S, Goldshmit Y, Wolfson E, Michaelson DM, Pinkas-Kramarski R 2020 Altered mitochondrial dynamics and function in APOE4-expressing astrocytes Cell Death Dis 11 578
236. Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D 2011 Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells J Neurosci 31 5970 5976
237. Sekine S, Wang C, Sideris DP, Bunker E, Zhang Z, Youle RJ 2019 Reciprocal roles of Tom7 and OMA1 during mitochondrial import and activation of PINK1 Mol Cell 73 1028 1043
238. Shefa U, Jeong NY, Song IO, Chung HJ, Kim D, Jung J, Huh Y 2019 Mitophagy links oxidative stress conditions and neurodegenerative diseases Neural Regen Res 14 749 756
239. Shen J, Du T, Wang X, Duan C, Gao G, Zhang J, Lu L, Yang H 2014 alpha-Synuclein amino terminus regulates mitochondrial membrane permeability Brain Res 1591 14 26
240. Shen Y, Ding M, Xie Z, Liu X, Yang H, Jin S, Xu S, Zhu Z, Wang Y, Wang D, Xu L, Zhou X, Wang P, Bi J 2019 Activation of mitochondrial unfolded protein response in SHSY5Y expressing APP cells and APP/PS1 mice Front Cell Neurosci 13 568
241. Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, Simard JM, Stern BJ 2014a Pilot study of intravenous glyburide in patients with a large ischemic stroke Stroke 45 281 283
242. Sheth KN, Kimberly WT, Elm JJ, Kent TA, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, del Zoppo G, Simard JM, Stern BJ, Mandava P 2014b Exploratory analysis of glyburide as a novel therapy for preventing brain swelling Neurocrit Care 21 43 51
243. Shpilka T, Du Y, Yang Q, Melber A, Uma Naresh N, Lavelle J, Kim S, Liu P, Weidberg H, Li R, Yu J, Zhu LJ, Strittmatter L, Haynes CM 2021 UPR(mt) scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans Nat Commun 12 479
244. Shutt T, Geoffrion M, Milne R, McBride HM 2012 The intracellular redox state is a core determinant of mitochondrial fusion EMBO Rep 13 909 915
245. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S 2006 Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease Neuron 49 489 502
246. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ 2018 Parkin and PINK1 mitigate STING-induced inflammation Nature 561 258 262
247. Soares JL, Oliveira EM, Pontillo A 2019 Variants in NLRP3 and NLRC4 inflammasome associate with susceptibility and severity of multiple sclerosis Mult Scler Relat Disord 29 26 34
248. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E 2011 Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity Nat Med 17 377 382
249. Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D'Amico D, Moullan N, Potenza F, Schmid AW, Rietsch S, Counts SE, Auwerx J 2017 Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity Nature 552 187 193
250. Soubannier V, Rippstein P, Kaufman BA, Shoubridge EA, McBride HM 2012 Reconstitution of mitochondria derived vesicle formation demonstrates selective enrichment of oxidized cargo PLoS One 7 e52830
251. Stone S, Jamison S, Yue Y, Durose W, Schmidt-Ullrich R, Lin W 2017 NF-kappaB activation protects oligodendrocytes against inflammation J Neurosci 37 9332 9344
252. Straub IR, Weraarpachai W, Shoubridge EA 2021 Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses Hum Mol Genet 30 687 705
253. Suomalainen A, Battersby BJ 2018 Mitochondrial diseases:the contribution of organelle stress responses to pathology Nat Rev Mol Cell Biol 19 77 92
254. Swerdlow RH 2012 Mitochondria and cell bioenergetics:increasingly recognized components and a possible etiologic cause of Alzheimer's disease Antioxid Redox Signal 16 1434 1455
255. Tajiri N, Borlongan CV, Kaneko Y 2016 Cyclosporine A treatment abrogates ischemia-induced neuronal cell death by preserving mitochondrial integrity through upregulation of the Parkinson's disease-associated protein DJ-1 CNS Neurosci Ther 22 602 610
256. Tan MS, Tan L, Jiang T, Zhu XC, Wang HF, Jia CD, Yu JT 2014 Amyloid-beta induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease Cell Death Dis 5 e1382
257. Tatton NA 2000 Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease Exp Neurol 166 29 43
258. Teske BF, Fusakio ME, Zhou D, Shan J, McClintick JN, Kilberg MS, Wek RC 2013 CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis Mol Biol Cell 24 2477 2490
259. Tian Y, Garcia G, Bian Q, Steffen KK, Joe L, Wolff S, Meyer BJ, Dillin A 2016 Mitochondrial stress induces chromatin reorganization to promote longevity and UPR(mt) Cell 165 1197 1208
260. Todkar K, Chikhi L, Desjardins V, El-Mortada F, Pepin G, Germain M 2021 Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs Nat Commun 12 1971
261. Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P, Raschke I, Merkwirth C, Ehses S, Krause F, Chan DC, Alexander C, Bauer C, Youle R, Langer T, Martinou JC 2009 SLP-2 is required for stress-induced mitochondrial hyperfusion EMBO J 28 1589 1600
262. Torralba D, Baixauli F, Villarroya-Beltri C, Fernandez-Delgado I, Latorre-Pellicer A, Acin-Perez R, Martin-Cofreces NB, Jaso-Tamame AL, Iborra S, Jorge I, Gonzalez-Aseguinolaza G, Garaude J, Vicente-Manzanares M, Enriquez JA, Mittelbrunn M, Sanchez-Madrid F 2018 Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts Nat Commun 9 2658
263. Torres-Peraza JF, Engel T, Martin-Ibanez R, Sanz-Rodriguez A, Fernandez-Fernandez MR, Esgleas M, Canals JM, Henshall DC, Lucas JJ 2013 Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus Brain 136 1161 1176
264. Tsai SJ 2017 Effects of interleukin-1beta polymorphisms on brain function and behavior in healthy and psychiatric disease conditions Cytokine Growth Factor Rev 37 89 97
265. Tyurin VA, Tyurina YY, Kochanek PM, Hamilton R, DeKosky ST, Greenberger JS, Bayir H, Kagan VE 2008 Oxidative lipidomics of programmed cell death Methods Enzymol 442 375 393
266. Tzeng TC, Hasegawa Y, Iguchi R, Cheung A, Caffrey DR, Thatcher EJ, Mao W, Germain G, Tamburro ND, Okabe S, Heneka MT, Latz E, Futai K, Golenbock DT 2018 Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice Proc Natl Acad Sci U S A 115 9002 9007
267. Ueda E, Ishihara N 2018 Mitochondrial hyperfusion causes neuropathy in a fly model of CMT2A EMBO Rep 19 e46502
268. Vaillant-Beuchot L, Mary A, Pardossi-Piquard R, Bourgeois A, Lauritzen I, Eysert F, Kinoshita PF, Cazareth J, Badot C, Fragaki K, Bussiere R, Martin C, Mary R, Bauer C, Pagnotta S, Paquis-Flucklinger V, Buée-Scherrer V, Buée L, Lacas-Gervais S, Checler F, et al. 2021 Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains Acta Neuropathol 141 39 65
269. Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR 2004a PINK1 mutations are associated with sporadic early-onset parkinsonism Ann Neurol 56 336 341
270. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, et al. 2004b Hereditary early-onset Parkinson's disease caused by mutations in PINK1 Science 304 1158 1160
271. Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D, Korsmeyer SJ, Przedborski S 2001 Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease Proc Natl Acad Sci U S A 98 2837 2842
272. Villace P, Mella RM, Kortazar D 2017 Mitochondria in the context of Parkinson's disease Neural Regen Res 12 214 215
273. Voet S, Mc Guire C, Hagemeyer N, Martens A, Schroeder A, Wieghofer P, Daems C, Staszewski O, Vande Walle L, Jordao MJC, Sze M, Vikkula HK, Demeestere D, Van Imschoot G, Scott CL, Hoste E, Gonçalves A, Guilliams M, Lippens S, Libert C, et al. 2018 A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation Nat Commun 9 2036
274. Volpe E, Sambucci M, Battistini L, Borsellino G 2016 Fas-Fas ligand:checkpoint of T cell functions in multiple sclerosis Front Immunol 7 382
275. von Herrmann KM, Salas LA, Martinez EM, Young AL, Howard JM, Feldman MS, Christensen BC, Wilkins OM, Lee SL, Hickey WF, Havrda MC 2018 NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson's disease NPJ Parkinsons Dis 4 24
276. Walko TD, 3rd, Bola RA, Hong JD, Au AK, Bell MJ, Kochanek PM, Clark RS, Aneja RK 2014 Cerebrospinal fluid mitochondrial DNA:a novel DAMP in pediatric traumatic brain injury Shock 41 499 503
277. Wallisch JS, Simon DW, Bayir H, Bell MJ, Kochanek PM, Clark RSB 2017 Cerebrospinal fluid NLRP3 is increased after severe traumatic brain injury in infants and children Neurocrit Care 27 44 50
278. Walsh JG, Muruve DA, Power C 2014 Inflammasomes in the CNS Nat Rev Neurosci 15 84 97
279. Wang DD, Jin MF, Zhao DJ, Ni H 2019a Reduction of mitophagy-related oxidative stress and preservation of mitochondria function using melatonin therapy in an HT22 hippocampal neuronal cell model of glutamate-induced excitotoxicity Front Endocrinol (Lausanne) 10 550
280. Wang MR, Zhang XJ, Liu HC, Ma WD, Zhang ML, Zhang Y, Li X, Dou MM, Jing YL, Chu YJ, Zhu L 2019b Matrine protects oligodendrocytes by inhibiting their apoptosis and enhancing mitochondrial autophagy Brain Res Bull 153 30 38
281. Wang P, Deng J, Dong J, Liu J, Bigio EH, Mesulam M, Wang T, Sun L, Wang L, Lee AY, McGee WA, Chen X, Fushimi K, Zhu L, Wu JY 2019c TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response PLoS Genet 15 e1007947
282. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X 2009 Impaired balance of mitochondrial fission and fusion in Alzheimer's disease J Neurosci 29 9090 9103
283. Wang X, Wang C, Chan HN, Ashok I, Krishnamoorthi SK, Li M, Li HW, Wong MS 2021 Amyloid-beta oligomer targeted theranostic probes for in vivo NIR imaging and inhibition of self-aggregation and amyloid-beta induced ROS generation Talanta 224 121830
284. Wasiak S, Zunino R, McBride HM 2007 Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death J Cell Biol 177 439 450
285. Wilkins HM, Koppel SJ, Weidling IW, Roy N, Ryan LN, Stanford JA, Swerdlow RH 2016 Extracellular mitochondria and mitochondrial components act as damage-associated molecular pattern molecules in the mouse brain J Neuroimmune Pharmacol 11 622 628
286. Wu A, Ye X, Huang Q, Dai WM, Zhang JM 2017 Anti-epileptic effects of valepotriate isolated from Valeriana jatamansi Jones and its possible mechanisms Pharmacogn Mag 13 512 516
287. Wu M, Liu X, Chi X, Zhang L, Xiong W, Chiang SMV, Zhou D, Li J 2018 Mitophagy in refractory temporal lobe epilepsy patients with hippocampal sclerosis Cell Mol Neurobiol 38 479 486
288. Xia X, Cui J, Wang HY, Zhu L, Matsueda S, Wang Q, Yang X, Hong J, Songyang Z, Chen ZJ, Wang RF 2011 NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKK Immunity 34 843 853
289. Yang X, Zhang M, Wei M, Wang A, Deng Y, Cao H 2020 MicroRNA-216a inhibits neuronal apoptosis in a cellular Parkinson's disease model by targeting Bax Metab Brain Dis 35 627 635
290. Yang X, Shi Q, Sun J, Lv Y, Ma Y, Chen C, Xiao K, Zhou W, Dong XP 2017 Aberrant alterations of mitochondrial factors Drp1 and Opa1 in the brains of scrapie experiment rodents J Mol Neurosci 61 368 378
291. Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante RJ, Kim AH, Friedlander RM 2014 Inhibition of mitochondrial protein import by mutant huntingtin Nat Neurosci 17 822 831
292. Ye X, Sun X, Starovoytov V, Cai Q 2015 Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains Hum Mol Genet 24 2938 2951
293. Yi HS, Chang JY, Shong M 2018 The mitochondrial unfolded protein response and mitohormesis:a perspective on metabolic diseases J Mol Endocrinol 61 R91 105
294. Yoneda T, Benedetti C, Urano F, Clark SG, Harding HP, Ron D 2004 Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones J Cell Sci 117 4055 4066
295. Yoshino H, Nakagawa-Hattori Y, Kondo T, Mizuno Y 1992 Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson's disease J Neural Transm Park Dis Dement Sect 4 27 34
296. Yuan Y, Zheng Y, Zhang X, Chen Y, Wu X, Wu J, Shen Z, Jiang L, Wang L, Yang W, Luo J, Qin Z, Hu W, Chen Z 2017 BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2 Autophagy 13 1754 1766
297. Yue P, Gao L, Wang X, Ding X, Teng J 2017 Intranasal administration of GDNF protects against neural apoptosis in a rat model of Parkinson's disease through PI3K/Akt/GSK3beta pathway Neurochem Res 42 1366 1374
298. Yue W, Chen Z, Liu H, Yan C, Chen M, Feng D, Yan C, Wu H, Du L, Wang Y, Liu J, Huang X, Xia L, Liu L, Wang X, Jin H, Wang J, Song Z, Hao X, Chen Q 2014 A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30 Cell Res 24 482 496
299. Zahedi A, Phandthong R, Chaili A, Leung S, Omaiye E, Talbot P 2019 Mitochondrial stress response in neural stem cells exposed to electronic cigarettes iScience 16 250 269
300. Zemirli N, Pourcelot M, Ambroise G, Hatchi E, Vazquez A, Arnoult D 2014 Mitochondrial hyperfusion promotes NF-kappaB activation via the mitochondrial E3 ligase MULAN FEBS J 281 3095 3112
301. Zhang M, He Q, Chen G, Li PA 2020a Suppression of NLRP3 inflammasome, pyroptosis, and cell death by NIM811 in rotenone-exposed cells as an in vitro model of Parkinson's disease Neurodegener Dis 20 73 83
302. Zhang X, Huang W, Fan Y, Sun Y, Ge X 2019a Role of GTPases in the regulation of mitochondrial dynamics in Parkinson's disease Exp Cell Res 382 111460
303. Zhang Y, Zhang M, Zhu W, Yu J, Wang Q, Zhang J, Cui Y, Pan X, Gao X, Sun H 2020b Succinate accumulation induces mitochondrial reactive oxygen species generation and promotes status epilepticus in the kainic acid rat model Redox Biol 28 101365
304. Zhang Y, Yao Y, Qiu X, Wang G, Hu Z, Chen S, Wu Z, Yuan N, Gao H, Wang J, Song H, Girardin SE, Qian Y 2019b Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing Nat Immunol 20 433 446
305. Zhao Q, Wang J, Levichkin IV, Stasinopoulos S, Ryan MT, Hoogenraad NJ 2002 A mitochondrial specific stress response in mammalian cells EMBO J 21 4411 4419
306. Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, Wong J, Ding S, Seki E, Schnabl B, Hevener AL, Greenberg HB, Kisseleva T, Karin M 2018 New mitochondrial DNA synthesis enables NLRP3 inflammasome activation Nature 560 198 203
307. Zhou Y, Lu M, Du RH, Qiao C, Jiang CY, Zhang KZ, Ding JH, Hu G 2016 MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease Mol Neurodegener 11 28
Keywords:

Alzheimer’s disease; apoptosis; mitochondrial dynamics; mito-inflammation; mitophagy; multiple sclerosis; neurodegeneration; Parkinson’s disease; UPRmt

Copyright: © 2022 Neural Regeneration Research