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Review Articles

Mitochondrial metabolism

a common link between neuroinflammation and neurodegeneration

Garabadu, Debapriya; Agrawal, Nidhi; Sharma, Anjali; Sharma, Sahil

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doi: 10.1097/FBP.0000000000000505
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Abstract

Introduction

Neurodegenerative diseases (NDs) are characterized by the progressive loss of neuronal function or structure in specific parts of the brain that eventually lead to cell death. NDs are considered as a large and diverse group of disorders. Proteinopathy is considered as one of the common attribute in NDs that include amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and multiple sclerosis (MS). The common manifestation in these NDs is the misfolding and aggregation of distinct proteins, resulting in the formation and deposition of insoluble fibrils, tangles and plaques. It has been observed that ALS is characterized by aggregates of RNA-binding proteins, whereas PD is associated with α-synuclein-containing aggregates and fibrils, AD with β-amyloid plaques, HD with aggregation-prone huntingtin with extended polyglutamine stretches, and MS with bassoon accumulation (Jellinger, 2009; Schattling et al., 2019). Interestingly, the accumulation of these neurotoxic proteins is mostly accompanied by critical impairment of mitochondrial integrity, mutations in the mitochondrial DNA, compromised oxidative phosphorylation, adenosine tri-phosphate (ATP) depletion, increased oxidative stress and subsequent cell death. In fact, effects on distinct respiratory chain complexes, mitochondrial transmembrane potential, biogenesis and dynamics have been attributed to most of the neurotoxic proteins (Guedes-Dias et al., 2015; Ryan et al., 2015). Further, the crucial role of mitochondria in neurodegenerative demise has been described in experimental and clinical conditions (Büttner et al., 2008; Humphrey et al., 2012; Büttner et al., 2013; Debattisti and Scorrano, 2013; Wager and Russell, 2013; Lane et al., 2015; Maglioni and Ventura, 2016).

Mitochondria a ‘key regulator' of neuroinflammation and neurodegeneration

It is well known that neurons have a high energy demand and are mostly powered by mitochondria. Defective mitochondria supply insufficient energy, leading to neuroinflammation and neuronal death (Attwell and Laughlin, 2001; Chen and Chan, 2006; Butterfield et al., 2014). Decrease in the brain energy metabolism and glucose uptake are reported in the pathogenesis of NDs, providing a clear link between NDs and energy metabolism (Petit-Taboué et al., 1998; Poon et al., 2006; Navarro and Boveris, 2007; Swerdlow, 2007; Yang et al., 2017). Mitochondria are sophisticated cellular organelles involved in a wide range of crucial cellular functions, and are also known as the power house of the cell (Selim and Hassaan, 2017). It has been reported that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against NDs (Yang et al., 2017). Mitochondria participate in β-oxidation of fatty acids, steroidogenesis, amino acid metabolism, heme biosynthesis, gluconeogenesis, and ketogenesis. Moreover, mitochondria also participate in downstream signaling, neuronal defence, adaptative programs, and neuronal death, highlighting their importance in the homeostasis in neuron and other brain tissues (Bravo-Sagua et al., 2017). In addition, mitochondrial dysfunction is known to generate high levels of reactive oxygen species (ROS) which are harmful to all cellular macromolecules (Adam-Vizi, 2005; Rodell et al., 2013). Recently, it has been suggested that diet, fasting and even exercise can influence the metabolic processes that occur inside mitochondria and therefore they can regulate the progress of neuroinflammation and neurodegeneration. The energy demands imposed by neurons require the well-orchestrated morphological adaptation and distribution of mitochondria (Khacho and Slack, 2018). Considering the above facts, it can be assumed that mitochondria are essential organelles for the maintenance of neuronal integrity, based on their manifold functions in regulating cellular metabolism and coordinating cell death and viability pathways. Accordingly, mitochondrial dysfunction and damage is associated with neurological disorders and can occur as a cause or consequence of NDs. Research has also revealed that mitochondria play a central role in orchestrating both innate and adaptive immune responses, thereby providing a link between neurodegenerative and neuroinflammatory processes. However, there is limited information regarding the mitochondrial metabolism-mediated neuroinflammation and neurodegeneration. Hence, understanding the interaction between mitochondrial metabolism and the mechanism that leads to neuroinflammation and neurodegeneration will help us to create an efficient pharmacotherapy.

Therefore, the present review for the first time extrapolates a probable relationship of altered mitochondrial metabolism in the pathogenesis of neuroinflammation and neurodegeneration.

Mitochondrial metabolism and neurodegeneration

Effect of mitochondrial pyruvate carrier in the genesis of neurodegenerative disorders

The alteration in mitochondrial pyruvate metabolism plays an important role in the pathophysiology of several NDs including AD and PD (Martin et al., 2005; Karsy et al., 2018; Fig. 1). It has been reported that an increased pyruvate level in cerebrospinal fluid is considered as a marker for AD (Parnetti et al., 1995), whereas a similar phenomenon has been observed in the blood serum of PD patients (Ahmed et al., 2009). Mitochondrial pyruvate metabolism is regulated by mitochondrial pyruvate carriers (MPCs) that modulate overall pyruvate carbon flux. The MPC is an inner-membrane transporter that facilitates pyruvate uptake from the cytoplasm into mitochondria (Bricker et al., 2012; Herzig et al., 2012). It is a central regulator of mitochondrial substrate utilization (Vacanti et al., 2014) and restrictions in mitochondrial pyruvate uptake can potentiate the use of fatty acids and a range of amino acids to fuel cellular energetics and biosynthesis (Vacanti et al., 2014; Yang et al., 2014; Gray et al., 2015; McCommis et al., 2015). Ghosh et al. (2016) hypothesized that targeting MPC, a key controller of cellular metabolism might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. MSDC-0160, a compound that specifically targets MPC to reduce its activity, leads to an immediate effect on mitochondrial metabolism associated with a later reduction in the overactivation of the mTOR pathway. The data suggest that activation of MPC induces autophagy as part of the response that prevents neurodegeneration. It has been supported that the anti-inflammatory effects of activated MPC are downstream of the immediate effects on metabolism. Activation of MPC had anti-inflammatory consequences in cellular and mouse models of inflammation and PD. The earliest measured effects involved direct increase in pyruvate metabolism and protection of oxidative metabolism followed by changes in the mTOR/AKT pathways (Ghosh et al., 2016).

Fig. 1
Fig. 1:
Pictorial representation of the mitochondrial pyruvate carrier (MPC): a reduced activity of MPC leads to the accumulation of pyruvate in the cytoplasm which promotes anaerobic glycolysis and thus aggravates neuroinflammation and neurodegeneration. AAT, aspartate aminotransferase; IDH 1, isocitrate dehydrogenase1; ROS, reactive oxygen species; RET, reverse electron transport; SDH, succinate dehydrogenase.

Additionally, mitochondrial pyruvate metabolism is also regulated by several enzymes including pyruvate dehydrogenase (PDH) and pyruvate carboxylase that can regulate overall pyruvate carbon flux. It has been reported that the activity of PDH is reduced without altering its level of expression in AD patients (Sheu et al., 1985). It has also been suggested that mutations in the proteins encoding genes regulating pyruvate metabolism may lead to neurological diseases (Gray et al., 2014). In addition, the advances in neuroimaging studies also indicate a significant role of brain energy metabolism in NDs. PET using different tracers such as 18F-fluorodeoxyglucose (FDG) has become the most common and efficient in-vivo approach to measuring the extent of alteration in brain energy metabolism in NDs (Hammes et al., 2017). Recently, it has also been suggested that 1-((2-fluoro-6-[18F] fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA- 23) is better than FDG as a radiotracer in evaluating the pyruvate metabolism in cell culture studies (Beinat et al., 2019). Taken these facts into, it can be assumed that imaging techniques could be a potential tool to evaluate the extent of aberration in pyruvate metabolism during NDs. These observations indicate that deficits in central nervous system pyruvate metabolism can contribute to NDs and MPC could be a potential target in the management of altered pyruvate metabolism to reduce the incidence and development of NDs.

Abnormal tricarboxylic acid cycle in mitochondria induces neurodegenerative disorders

The tricarboxylic acid (TCA) cycle is the main metabolic pathway for the production of ATP via the electron transport chain (ETC). Glucose is converted to pyruvate, and the oxidative decarboxylation of pyruvate to acetyl CoA by the PDH complex (PDHC) is the entry step into the TCA cycle. The PDHC provides the acetyl CoA from pyruvate that initiates the TCA cycle in neurons. PDHC is composed of multiple subunits and is controlled by inhibitory kinases and activating phosphatases that continuously regulate its activity (Holness and Sugden, 2003). It is well known that glucose is the principle source of energy to the brain and therefore PDHC plays a critical role in the function of TCA cycle in the neurons. Naseri et al. (2016) suggests that PDHC is diminished in autopsy brains of HD patients and is thus assumed to play a critical role in the pathophysiology of HD (Sorbi et al., 1983; Butterworth et al., 1985).

The remainder of the cycle consists of the following enzymes in order: citrate synthase, aconitase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase complex (KGDHC), succinyl thiokinase, succinate dehydrogenase (SDH), fumarate hydratase, and malate dehydrogenase. Since all of the enzymes of TCA cycle are responsible for catalyzing sequential reactions, they have been proposed to be organized in supramolecular complexes termed metabolons (Lyubarev and Kurganov, 1989). It has been reported that a decline of mitochondrial oxidation and increase in the oxidative stress are important functional markers of aging and common risk factors of age related NDs (Blass, 1993; Beal, 1995). It has also been reported that aconitase activity is severely decreased in brain of HD patients, whereas beings found to be normal in PD subjects (Schapira, 1999). Further, it has been suggested that a deficiency in isocitrate dehydrogenase (IDH) can cause a lack of availability of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) for NADPH-dependent antioxidant enzymes and this drives oxidative stress in the mitochondria of dopaminergic neurons in the brain. This oxidative stress intensifies mitochondrial dysfunction and thus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neuronal death during PD. Thus IDH is crucial in regulating redox status and dopaminergic neuronal function. Systems with down-regulated IDH may be useful models in future studies of mitochondria-targeted antioxidants and the treatment or prevention of NDs (Kim et al., 2016).

The KGDHC is, a rate-limiting enzyme of the TCA cycle, critically involved in the pathogenesis of several NDs including AD. It is reported that the activity of KGDHC is reduced in a number of NDs including AD and PD (Gibson et al., 1988; Butterworth and Besnard, 1990; Gibson et al., 2003). It has been revealed that the specific nitration on the tyrosine residues in KGDHC treated with peroxynitrite inhibited its activity in a dose-dependent manner. This process can be partially reversed by subsequent addition of reduced glutathione. KGDHC is likely to contribute to its reversal by acting as a denitrase in the presence of reduced glutathione in neurons (Shi et al., 2011). Therefore, it is needed to regulate the activity of KGDHC in neurons for preventing neurodegeneration.

SDH is another TCA cycle enzyme that possesses a most promising role in addition to the ETC. SDH, also known as complex II or succinate:quinone oxidoreductase, is an enzyme involved in both oxidative phosphorylation and TCA cycle, the processes that generate energy. SDH is a multi-subunit enzyme, which requires a series of proteins for its proper assembly at several steps. This enzyme has medical significance as it is involved in neurodegeneration related to SDH malfunction (Moosavi et al., 2019). Therefore, a dysfunction in SDH activity can impair mitochondrial activity, ATP generation and energy homeostasis in the neurons. The concentration of malate, fumarate, citrate, and specifically oxaloacetate are the known factors that can influence the activity of SDH (Gutman et al., 1971; Nulton-Persson and Szweda, 2001). Moreover, the activity of SDH can influence excessive lipid synthesis during NDs. Inhibition of SDH leads to malate and fumarate accumulation in neurons (Van Vranken et al., 2014). For ATP generation, a low concentration of fumarate is needed (Rottenberg and Gutman, 1977). Therefore, high levels of fumarate in matrix can decrease ATP production. Further, accumulation of succinate in neurons provokes the generation of ROS (Ralph et al., 2011). SDH can increase the production of superoxide by other complexes, I and III, of the ETC (Dröse et al., 2011). In addition, mutation in SDH correlates with the onset of NDs. Therefore, SDH could behave as a key regulator in neuroprotection in NDs (Jodeiri Farshbaf and Kiani-Esfahani, 2018).

Thiamin is an essential nutrient and indispensible for normal growth and development of the organism due to its multifactorial role in major biochemical and physiological processes. Humans must obtain thiamin from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamin deficiency can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. Thiamin is a cofactor of key metabolic enzymes and thiamin deficiency leads to alterations in brain glucose metabolism (Kinnersley and Peters, 1929; Hakim and Pappius, 1981). Thiamin deficiency causes impairment in cerebral oxidative metabolism that leads to selective neuronal loss and neurological symptoms. In the brain, thiamin deficiency causes a cascade of events including mild impairment of oxidative metabolism, neuroinflammation, and neurodegeneration, which are commonly observed in NDs, such as AD and PD. Thiamin metabolites may serve as promising biomarkers for NDs and thiamin supplementations exhibits therapeutic potential for NDs patients (Liu et al., 2017).

Alterations in the TCA cycle and glutamate metabolism are observed under oxidative stress in motor neurons. The glutamate–glutamine cycling pathway between neurons and astroglia has been studied extensively in vivo, in cell culture, and in brain slices using isotope tracers (Lapidot and Gopher, 1994). Despite the large amount of evidence for its existence, early kinetic studies considered that the glutamate–glutamine cycling flux is small and makes only a minor contribution to brain energy metabolism. Consistent with this notion, the fraction of glutamate participating in the glutamate–glutamine cycle is considered small, leading to the conceptualization of a neurotransmitter glutamate pool and a separate metabolic glutamate pool (Lapidot and Gopher, 1994). It is well known that glutamate is the principal excitatory neurotransmitter in brain. At low concentrations glutamate excites virtually all neurons in the central nervous system. Excessive activation of glutamate receptors by glutamate can result in a number of pathological conditions and can lead to cell death. As a zwitterionic molecule glutamate cannot diffuse across cell membranes, and it is well-understood that glutamate uptake plays an important role in regulating the extracellular concentration of glutamate in the brain. Glutamate released by neurons is rapidly taken up by astroglial cells, via high-affinity Na+-dependent glutamate transporters. Subsequently, glutamate is either converted into glutamine by glutamine synthetase, which is exclusively localized in glial cells or oxidized by assimilation into the Krebs cycle located in the mitochondria of astroglial cells. Although glutamate is rapidly synthesized from glucose in neural tissues the biochemical processes for replenishing the neurotransmitter glutamate after glutamate release involve the glutamate–glutamine cycle. Glutamine, formed by amidization of glutamate, is readily discharged from astroglial cells by facilitated diffusion via Na+- and H+-coupled, electroneutral systems-N transporters. Glutamine readily enters into nerve terminals mainly by electrogenic systems-A transporters (Chaudhry et al., 2002). There glutaminase converts it back into glutamate which can be again used for neuronal transmission or assimilated into the neuronal Krebs cycle. Further, it has been well-documented from the imaging studies that glutamate–glutamine cycle can regulate oxidative metabolism in astrocyte and neuron in neurological disorders (Sonnay et al., 2018).

The TCA cycle is highly integrated so that just measuring one enzyme does not give the full impact of the disease on the TCA cycle or the impact of the change on the disease process (Bubber et al., 2004). However, although the critical role of mitochondrial TCA cycle is well established in most of the NDs (Fig. 2), its significance in the pathogenesis of these diseases yet to be proved.

Fig. 2
Fig. 2:
Pictorial representation of tricarboxylic acid cycle (TCA): abnormality in the function of the TCA cycle leads to both neuroinflammation and neurodegeneration, which is mostly due to the aberrant activity of the enzymes involved. AAT, aspartate aminotransferase; ACO2, aconitase; IDH 1, isocitrate dehydrogenase1; KGDHC, α-ketoglutarate dehydrogenase complex; ROS, reactive oxygen species; RET, reverse electron transport; SDH, succinate dehydrogenase.

Altered mitochondrial malate-aspartate shuttle induces neurodegenerative disorders

Cellular energy metabolism is confined to either the cytoplasm or the mitochondria. Cells must maintain a balance of metabolic intermediates between the cytosol and the mitochondria to enable lactate metabolism to continue, and an inability to maintain this balance results in impairment of mitochondrial metabolism. Pyruvate is transported into mitochondria by specific transport proteins and is metabolized within the mitochondria. In contrast, lactate is converted to pyruvate within the cytosol, with the concomitant conversion of nicotinamide adenine dinucleotide (NAD) from its oxidized form (NAD+) to its reduced form (NADH). The pyridine nucleotides (NAD, NADH, nicotinamide adenine dinucleotide phosphate, and NADPH) are compartmentalized, in addition to many enzymes existing in either the cytoplasm or mitochondria. It has been suggested that intact mitochondria are impermeable to NADH (Lai et al., 1989). It is well known that the most common mitochondrial shuttle, the malate-aspartate shuttle (MAS) transfers NADH across the inner mitochondrial membrane for subsequent oxidation and also regenerates the NAD in the cytoplasm that is required for further cytoplasmic conversion of lactate to pyruvate or for Embden–Meyerhof pathway activity in the neuron. This shuttle involves four enzymes mitochondrial aspartate aminotransferase and malate dehydrogenase, and cytoplasmic aspartate aminotransferase and malate dehydrogenase (Fig. 3). In the absence of these enzymes, the NAD pools within the axoplasm quickly become exhausted and prevent the neuron from using either lactate or glucose as an energy source. Inhibition of the MAS impairs the utilization of glucose, which is a main source of metabolic energy in the neurons thus favoring the anaerobic formation of lactate over the aerobic option of TCA cycle. Under such conditions the oxidative metabolism of pyruvate via the TCA cycle, which is more efficient in terms of ATP production, decreases (McKenna et al., 2006).

Fig. 3
Fig. 3:
Pictorial representation of the malate-aspartate shuttle (MAS): the MAS is the main pathway for the transfer of reducing equivalents in the form of NADH from the cytosol into the mitochondria. Glycolysis in the cytosol generates NADH, which is transported into mitochondria by the transamination of aspartate to malate. A reduced activity in the MAS may contribute to the pathophysiology of neuroinflammation and neurodegeneration. AAT, aspartate aminotransferase; IDH 1, isocitrate dehydrogenase1; mAAT, mitochondrial aspartate aminotransferase; MDH 1, malate dehydrogenase 1; MDH 2, malate dehydrogenase 2; NADH, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; RET, reverse electron transport; SDH, succinate dehydrogenase.

The mitochondrial aspartate-glutamate carrier Aralar/AGC1 is a regulatory component of the MAS found mostly in brain. It is reported that Aralar deficiency causes a shutdown of brain shuttle activity and global cerebral hypomyelination in preclinical and clinical conditions (Juaristi et al., 2017). A lack of neurofilament-labeled processes is detected in the cerebral cortex, but whether different types of neurons are differentially affected by Aralar deficiency is still not clear. Adult Aralar-hemizygous mice exhibit an abnormal dopaminergic activity in striatum and promote sensitivity to amphetamine. Further, Aralar deficiency causes a fall in glutathione reduction and vesicular monoamine transporter-2 in striatum that may relate to a failure to produce mitochondrial NADH and to an increase in ROS in the cytosol and thus could be a target for the nigrostriatal dopaminergic system (Llorente-Folch et al., 2013). Moreover, the MAS also plays a significant role in the pathogenesis of other neurological disorders such as epilepsy (Juaristi et al., 2017). However, its role is yet to be established in the pathogenesis of NDs and this could be a potential target in the process of drug discovery in such disorders (Fig. 3).

Significance of mitochondrial urea cycle in the development of neurodegenerative disorders

The urea cycle is a biochemical reaction that produces urea from ammonia (Fig. 4). It is the common pathway for the excretion of waste nitrogen for detoxication that cannot be used to build amino acids (Kenny et al., 2002). The first and second steps of the urea cycle occur in mitochondria, whereas the other three steps occur in the cytoplasm. First, ammonia combines with ATP and HCO3 to form carbamoyl phosphate with the help of enzyme carbamoyl phosphate synthetase I. Carbamoyl phosphate reacts with ornithine to produce citrulline in presence of ornithine transcarbamoylase. Subsequently, citrulline is transported out of mitochondria and then reacts with aspartate to form argininosuccinate in presence of the enzyme argininosuccinate synthetase. Thereafter, argininosuccinate is converted by argininosuccinate lyase into fumarate and arginine. In the final step, arginase converts arginine into ornithine and urea. It has been suggested that excretion of excess ammonia is necessary for neuronal survival; there are several causes of increased ammonia levels in brain, and therefore different approaches have been developed to this problem (Natesan et al., 2016).

Fig. 4
Fig. 4:
Pictorial representation of urea cycle (ornithine cycle): an exaggerated activity of the urea cycle can cause the accumulation of urea in neurons, which could be a contributing factor for the genesis of neuroinflammation and neurodegeneration. AAT, aspartate aminotransferase; IDH 1, isocitrate dehydrogenase1; mAAT, mitochondrial aspartate aminotransferase; MDH 2, malate dehydrogenase 2; NADH, nicotinamide adenine dinucleotide; NO, nitric oxide; ROS, reactive oxygen species; RET, reverse electron transport; SDH, succinate dehydrogenase.

It has been suggested that brain urea cycle plays a critical role in the pathophysiology of several NDs including AD and HD (Bichell et al., 2017; Polis et al., 2018). It has been shown that the normal human brain has very low or no ornithine transcarbamoylase activity, thus preventing urea cycle activity (Bensemain et al., 2009). However, arginase, one of the main urea cycle enzymes, is found to be hyperactive in the hippocampus of AD patients (Polis et al., 2018; Polis et al., 2019). Further, it has been demonstrated that there is accumulation of urea in several brain regions of HD patients (Patassini et al., 2015). It has also been reported that a mutation in the huntingtin gene caused a significant reduction in the neuronal manganese and may contribute to the hyperactive state of arginase in the neuron, which ultimately leads to increased levels of urea in the brain (Bichell et al., 2017). Hence, it can be assumed that the brain urea cycle could be a potential therapeutic target in the management of NDs.

Mitochondrial metabolism and neuroinflammation

Mitochondrial metabolism influences the activity of mononuclear phagocytes, and the metabolites that they produce have key signaling roles in innate and adaptive immunity systems, and thus in inflammation. Neuroinflammation has been associated with the cause or consequence of chronic oxidative stress. Microglial cells are the main source of reactive oxygen and nitrogen species, pro-inflammatory cytokines and glutamate, all of which are neurotoxic (Braak et al., 2003; Magro et al., 2004; Qian et al., 2007; Panaro et al., 2008; Querfurth and LaFerla, 2010; Chastain et al., 2011; Saccon et al., 2013; González et al., 2014; Chen et al., 2016). Moreover, astrocyte function is primarily focused on the preservation of neural environments, including maintenance of the extracellular milieu, and buffering of neurotransmitters and ions (Suzuki et al., 2011). These functions require energy and are therefore reliant on the presence of functional mitochondria in the astrocyte. Perturbations in astrocyte mitochondrial functions, therefore, may adversely impact neuroprotective services provided by the astrocyte. Thus, it is evident that mitochondrial impairment and neuroinflammation are inter-related (Di Filippo et al., 2010; Ye et al., 2016; Hunter et al., 2017). Hence, mitochondrial metabolism could be a potential target to attenuate neuroinflammation in several neurological disorders.

It has been suggested that MPC regulates autophagy and neuroinflammation, and thus improves the survival of substantia nigra dopaminergic neurons during PD (Ghosh et al., 2016). Further, MSDC-0160 attenuates neuroinflammation, astrogliosis and microgliosis in PD subjects (Quansah et al., 2018). In addition, MSDC-0160 pretreatment reduced LPS-induced inflammatory markers. Prevention of pyruvate entry into mitochondria may rewire cellular homeostasis by changing the metabolism of amino acids that supply different sources of carbon to the mitochondrial metabolic pathway. Indeed, pyruvate entry inhibition may cause changes in glutamine and glutamate utilization and fatty acid oxidation, which could in turn trigger downstream changes in autophagy and inflammatory pathways in neuronal and glial cells. It has been reported that MPC inhibitors such as the first generation thiazolidinediones, MSDC-0160 and UK-5099, cause significant changes in mitochondrial metabolism and cellular homeostasis (Vacanti et al., 2014; Ghosh et al., 2016; Divakaruni et al., 2017). It has been also shown that MSDC-0160-attenuated neurodegeneration in multiple cell and animal models of PD by a process that includes augmentation of autophagy and reduction of inflammation (Ghosh et al., 2016). These effects occurred in both genetic-and neurotoxin-based PD models. These actions of MSDC-0160 involve effects on both neurons and glial cells. It is clear that glial cells and neurons communicate in vivo, and it is possible that MSDC-0160 could have influenced either neuronal survival or glial activation states indirectly. However, in-vitro experiments in which neurons and glia are cultured separately indicate that MSDC-0160 has direct effects on both cell types. The data strongly suggest that modulation of the activity of MPC can improve the attributes of PD (Chen et al., 2012). Therefore, MPC appears to be a particularly striking molecular target for disease modification in PD.

A previous study suggests that MAS plays an important role in the number of biological processes including glial synthesis of glutamate and glutamine (Hertz and Rothman, 2017). Further, it has been reported that aminooxyacetic acid, a widely used MAS inhibitor, can decrease the levels of pro-inflammatory markers such as inducible nitric oxide synthase, tumor necrosis factor-α, and cyclooxygenase-2 (Shang et al., 2017). However, it remains unclear how MAS is involved in microglial activation. It is believed that NADH can contribute to several biological processes, including microglial activation (Lu et al., 2008). It is proposed that MAS can regulate microglial activation by modulating the cytosolic and mitochondrial levels of NADH and thus can be considered as a novel target for neuroinflammation in NDs (Shang et al., 2017).

It has also been suggested that IDH plays a key role in inducing gliomas and neurodegeneration. IDH dysfunction has been linked to various NDs associated with uncontrolled inflammatory responses, such as the excessive generation of pro-inflammatory cytokines. It has been demonstrated that IDH contributes to the regulation of pro-inflammatory mediators in microglia. The down-regulation of IDH decreases the pro-inflammatory response in BV-2 and primary microglial cells. Furthermore, IDH deficiency down regulates proinflammatory mediators (Chae et al., 2018). Therefore, these findings indicate that IDH could be a promising target for the regulation of pro-inflammatory responses in microglial cells.

Conclusion

The present review for the first time summarizes the potential contribution of mitochondrial metabolic pathways in the pathogenesis of neuroinflammation and neurodegeneration (Fig. 5). A reduced activity of the MPC can contribute to the pathogenesis of neuroinflammation and neurodegeneration. Further, the reduced activity of TCA cycle enzymes can contribute to the overall abnormality in TCA cycle activity and later can contribute to the pathophysiology of neurodegeneration and neuroinflammation. Furthermore, there is a decrease in the activity of the MAS and increase in the urea cycle in the pathobiology of neuroinflammation and neurodegeneration in several NDs. It is pertinent to note that these mitochondrial metabolism markers could be considered as potent biomarkers to diagnose both neuroinflammation and neurodegeneration in several NDs. Moreover, they can be considered as potential therapeutic targets in the management of NDs.

Fig. 5
Fig. 5:
A chart summary of the mitochondrial metabolism that contributes to the pathogenesis of neuroinflammation and neurodegeneration: both a decrease in the activity of the MPC and MAS and a significant increase in abnormality of the TCA cycle function and urea cycle can cause neuroinflammation and neurodegeneration. MAS, malate-aspartate shuttle; MPC, mitochondrial pyruvate carrier; TCA, tricarboxylic acid.

Acknowledgments

N.A., A.S. and S.S. are thankful to the GLA University, Mathura, Uttar Pradesh, India for the financial assistantship.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

brain; citric acid cycle; malate-aspartate shuttle; mitochondrial metabolism; neurodegeneration; neuroinflammation; pyruvate metabolism; urea cycle

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