Bioenergetics, Mitochondrial Dysfunction, and Oxidative Stress in the Pathophysiology of Septic Encephalopathy
Bozza, Fernando A.*†; D’Avila, Joana C.*‡; Ritter, Cristiane§∥; Sonneville, Romain¶; Sharshar, Tarek¶; Dal-Pizzol, Felipe§∥
*Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz and Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural; †D’Or Institute for Research and Education (IDOR); and ‡Laboratório de Imunofarmacologia, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro; and §Laboratório de Fisiopatologia Experimental and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense; and ∥Intensive Care Unit, Hospital São José, Criciúma, Santa Catarina, Brazil; and ¶Service de Réanimation Médicale, Hôpital Raymond Poincaré, Garches, France.
Address reprint requests to Fernando A. Bozza, MD, PhD, Intensive Care Unit, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Rio de Janeiro, Brazil. E-mail: firstname.lastname@example.org; email@example.com. Or Felipe Dal-Pizzol, MD, PhD, Laboratório de Fisiopatologia Experimental, Unidade Acadêmica de Ciências da Saúde, Universidadedo Extremo Sul Catarinense, Criciúma, Santa Catarina, Brazil. E-mail: firstname.lastname@example.org.
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Instituto Nacional de Ciência e Tecnologia (INCT) em Biologia Estrutural e Bioimagem, e INCT em Translacional em Medicina, Brazil.
ABSTRACT: Sepsis is a major cause of mortality and morbidity in intensive care units. Acute and long-term brain dysfunctions have been demonstrated both in experimental models and septic patients. Sepsis-associated encephalopathy is an early and frequent manifestation but is underdiagnosed, because of the absence of specific biomarkers and of confounding factors such as sedatives used in the intensive care unit. Sepsis-associated encephalopathy may have acute and long-term consequences including development of autonomic dysfunction, delirium, and cognitive impairment. The mechanisms of sepsis-associated encephalopathy involve mitochondrial and vascular dysfunctions, oxidative stress, neurotransmission disturbances, inflammation, and cell death. Here we review specific evidence that links bioenergetics, mitochondrial dysfunction, and oxidative stress in the setting of brain dysfunctions associated to sepsis.
Sepsis is associated with multiple organ dysfunctions including acute brain dysfunction, termed here sepsis-associated encephalopathy (SAE), which is an independent predictor of death (1). Recently, a large prospective cohort study associated severe sepsis with long-term cognitive impairment and functional disability among survivors (2). In addition, sepsis, independently of other risk factors, significantly contributes to long-term neurodevelopmental impairment also in preterm infants (3). Thus, it is possible that a large spectrum of disease occurs, going from a mild transitory to irreversible brain dysfunction, progressing from acute delirium to chronic cognitive decline. Despite its importance, SAE has been neglected mainly because there are no precise clinical diagnoses of damage to the brain during sepsis (4). Sepsis-associated encephalopathy pathophysiology is poorly understood, but several mechanisms have been proposed, such as mitochondrial and vascular dysfunction, oxidative damage, neurotransmission disturbances, inflammation, and cellular death (5). Here we review evidence that links bioenergetics, mitochondrial dysfunctions, and oxidative stress in the setting of brain dysfunction associated to sepsis.
Bioenergetics, mitochondrial dysfunctions, and oxidative stress as key mechanisms of septic encephalopathy
Brain function is almost totally dependent on a continuous supply of glucose and oxygen from the arterial circulation. Although the brain represents only 2% of the body weight, it receives 15% of the cardiac output and consumes 20% of total body oxygen and 25% of total body glucose. As glycogen stores are low (~3 mmol/kg) and exclusive to astrocytes (6), brain glucose supply must be ensured by continuous cerebral blood flow. The brain contains different types of glucose transporters (GLUTs): GLUT 1 is localized on the microvessels and glia, and GLUT 3 is the neuronal isoform (7). Nevertheless, the brain relies on alternative sources of energy substrates, such as phosphocreatine, synthesized by creatine kinase enzymes located at strategic intracellular sites to couple areas of high-energy expenditure to the efficient regeneration of ATP. The creatine kinase/phosphocreatine system plays an important role in energy buffering and cellular bioenergetics because phosphocreatine can rapidly donate a phosphate group to ADP, creating a compartmentalized ATP synthesis, which is particularly important in cells with high and fluctuating energy requirements such as neurons (8).
Neurotransmission and ionic homeostasis account for most of brain energy expenditure. Glutamate is the major excitatory amino acid, and its extracellular levels must be tightly regulated to maintain brain tissue homeostasis. The uptake of glutamate from the extracellular space is coupled to an inward sodium cotransport that in turn activates the Na+/K+ ATPase pump to normalize ionic gradients across plasma membranes in an ATP-dependent manner. Thus, glutamatergic neurotransmission accounts for a considerable part of energy consumption in the brain. Among the central nervous system (CNS) cell types, neurons are the most oxygen-dependent cells, and numerous studies demonstrate a strong metabolic cooperation between astrocytes and neurons in terms of neurotransmitter reuptake, antioxidant defense, and energy substrate delivery, and all these processes critically depend on energy metabolism (9). Proinflammatory cytokines can modulate astrocytes’ energy metabolism and cellular stress defenses, which may contribute to increased neuronal vulnerability and neurodegeneration (10). In pathological condition associated to neuroinflammation, such as in sepsis, excitatory glutamatergic neurotransmission appears to be increased (5), and this can be both cause and consequence for a bioenergetics crisis and directly affect brain function.
As a major catabolic insult, with disturbances in carbohydrate, lipid, and protein metabolism, sepsis leads to a peripheral bioenergetics crisis and extensive muscle protein breakdown. Classically, altered mental status has been associated to higher levels of plasma aromatic amino acids and normal or low-normal levels of branched-chain amino acids in septic patients. The decrease in branched-chain amino acid/aromatic amino acid ratio has been also associated to an imbalance of neurotransmitters including norepinephrine, dopamine, and serotonin (11). More recently, kynurenine, a product of tryptophan metabolism induced by proinflammatory mediators, was shown to accumulate in the brain in the acute phase of sepsis due to the loss of blood-brain barrier (BBB) integrity common in sepsis. This study showed that increased kynurenine pathway activity was an independent predictor of greater duration of acute brain dysfunction (12). Kynurenine is also an endothelial-relaxing factor that was recently shown to contribute to hypotension in human sepsis (13).
Cerebral blood flow autoregulation and normal mitochondrial function are critical events for the maintenance of brain function and tissue viability. Damage to the mitochondrial respiratory chain is a significant factor in the pathogenesis of many neurodegenerative diseases (14). Following inhibition of mitochondrial respiration, astrocytes respond by increasing their glycolytic metabolism using glycolytically generated ATP to maintain their mitochondrial membrane potential, whereas neurons divert glucose to the pentose phosphate pathway to generate nicotinamide adenine dinucleotide phosphate (NADPH), the cofactor necessary for the regeneration of the antioxidant glutathione (15). It has been suggested that glycolytically generated ATP is more important than that generated by oxidative phosphorylation in providing energy for glutamate uptake both in astrocytes and in neurons (16). Therefore, under systemic inflammatory conditions, especially when combined with hemodynamic instability as in septic shock, where oxygen and glucose delivery usually are limited, neurons seem to be more sensitive than glial cells to metabolic disturbances (17).
Many evidence points to a critical role of mitochondria activity in the pathogenesis of multiple organ dysfunction syndrome (MODS) (18). Several studies in experimental models and patients have shown the occurrence of mitochondrial dysfunctions in different tissues associated with severity of sepsis and septic shock (18–22). Mitochondrial dysfunctions in sepsis occur by several mechanisms. Although many studies point to dysfunctions in the electron transport chain (ETC) (21), alternative mechanisms include altered mitochondrial structure (swelling) (20), reversible inhibition of ETC complex IV or cytochrome c oxidase (23), oxidative inhibition of mitochondrial dehydrogenases and adenine nucleotide transporters, and decreased cytochrome content and respiratory uncoupling (22, 24) by activities such as uncoupling proteins and the permeability transition pore opening, which increases the permeability of inner mitochondrial membrane leading to proton leak and loss of mitochondrial membrane potential (22, 24). The consequences of mitochondrial dysfunction are numerous and include oxidative stress, cellular Ca2+ dys-homeostasis, promotion of apoptosis, and metabolic failure (Fig. 1). Recently, treatments for mitochondrial dysfunctions have been proposed as an emerging possibility to treat MODS (25).
Alterations in mitochondrial function occur in different levels depending on the tissue and on the timing after disease onset. A study with endotoxemic rats showed a rapid onset of mitochondrial dysfunction in the ETC complex I and IV in the rostral ventrolateral medulla, the medullary origin of sympathetic vasomotor tone (26), suggesting that nitric oxide (NO) and proinflammatory cytokines could be inducing mitochondrial reactive oxygen species (ROS) production and dysfunction. In experimental polymicrobial sepsis (cecal ligation and puncture [CLP]) in mice, we demonstrated a reduction in the efficiency of oxidative phosphorylation due to increased permeability of inner mitochondrial membrane and reduction in cytochrome content and complex IV activity in the brain tissue 24 h after sepsis onset (22). In this study, we did not observe increased mitochondrial ROS production, suggesting that other pathways such as the NADPH oxidase (NOX) could be responsible for the oxidative stress observed in the brain tissue of septic rodents (27). In another study with the CLP model in rats, we observed decreased complex I activity late after sepsis induction and increased creatine kinase activity more pronounced 6 h after sepsis onset, in several brain structures (21), corroborating previous finding that early mitochondrial ETC dysfunction and oxidative stress might be associated to acute brain dysfunction in SAE. These studies used fluid resuscitation to avoid hypotension, so it is possible that the mitochondrial dysfunctions observed are secondary to the inflammatory response and not to low blood pressure. Besides its role in energy metabolism, mitochondrion is an important calcium-buffering system in brain cells. Thus, alterations in mitochondrial function may contribute directly to derangements in calcium homeostasis and neurodegeneration (28).
Oxidative stress can impair mitochondrial function by inducing structural changes with ensuing loss of activity of a number of mitochondrial enzymes, compromising ATP synthesis (29). In addition, the direct action of ROS in mitochondrial membrane lipids and proteins may result in the activation of apoptotic cascades. In addition to targets of oxidative stress, mitochondria are also major sources of ROS in the intracellular space. Inducible nitric oxide synthase (iNOS) expression is increased in the brain during sepsis (30), raising the levels of NO and peroxynitrite, which have well-described effects on inhibiting mitochondria ETC (31). Nitric oxide also works as an energy metabolism switch inhibiting mitochondria activity and stimulating glycolysis (32). Figure 2 summarizes the mechanisms and consequences of mitochondrial dysfunction during sepsis.
Brain tissue has unique characteristics that make it more susceptible to oxidative damage during sepsis, such as low levels of antioxidant defenses compared with other organs (33) and a high rate of oxygen consumption. Experimental and clinical studies demonstrate that MODS in sepsis is associated with increased production of ROS and depletion of antioxidants, leading to oxidative stress (34). Despite the fact that several neuroinflammatory conditions can induce oxidative damage in the brain, these data are mainly from models in which lipopolysaccharide (LPS) is injected directly into the brain, which does not reflect the alterations observed in sepsis. Direct evidence of oxidative damage in the brain in relevant models of sepsis or human patients is limited.
Lipopolysaccharide administered systemically is able to induce oxidative damage as early as 2 h (35), and up to 24 h, and such damage is reversible by the administration of antioxidants (36). In addition, a single injection of LPS induces antioxidant enzyme depletion that can be sustained several hours after LPS administration (37). In the CLP rodent model of sepsis, there is an increase in superoxide (O2−), nitrite, and lipid peroxidation content in the brain capillaries until 48 h after sepsis induction (38). Glutathione concentration is significantly decreased even at longer times (48 h) (39). In contrast, we observed maximum oxidative damage around 6 h in the course of sepsis (27). At longer times after CLP (10 days), there is some evidence of oxidative damage in the hippocampus, but not the other brain regions (40).
Brain oxidative damage was also determined in septic patients. Ascorbate levels were significantly lower in cerebrospinal fluid (CSF) in patients with septic encephalopathy, being correlated with the severity of neurologic symptoms (41). Postmortem brains of septic patients presented higher expression of iNOS in endothelial cells in septic shock when compared with nonseptic shock patients (30). In septic children, there was a significant increase in the CSF levels of NO and lipid peroxidation, and patients with signs of brain dysfunction have increased levels of these markers compared with sepsis only (42).
Thus, oxidative damage occurs consistently in different models of sepsis as well as in septic humans and is associated with both increase in the production of reactive oxygen and nitrogen species and decrease in antioxidant defense systems. As well as observed in others organs, oxidative damage could be associated with the development of brain dysfunction during sepsis.
Molecular mechanisms of brain dysfunction in sepsis
NO-driven oxidative stress
Nitric oxide is produced by glia under proinflammatory stimuli, and this is associated with increased cellular membrane damage and a marked decrease in the intracellular levels of reduced glutathione and ATP (43). In neuron-glial coculture, LPS-induced NO from glial cells generated oxidative damage in the neurons (44). Reactive oxygen species are involved in the microglial intracellular signaling to induce iNOS (45). Microglia activated with LPS produce more O2− via NOX1-dependent NOX, which enhances iNOS expression and secretion of interleukin 1β (45). Superoxide activates a ROS-dependent PI3-K and p38 MAPK signaling pathways and that NOX-derived ROS functions as an upstream regulator of both these kinases (46). This pathway has dual functions. The NADPH-derived O2− can initiate a cascade of processes that culminates with iNOS expression but can also be involved in the formation of peroxynitrite in LPS-activated microglia (47). In addition to iNOS, there is preliminary evidence that inhibitors of the constitutive isoforms, the calcium/calmodulin controlled isoenzymes eNOS (endothelial NOS) and nNOS (neuronal NOS), protected the brain against oxidative stress evoked by LPS, suggesting involvement of constitutive NOS in septic encephalopathy (48).
Inhibition of brain mitochondrial function during sepsis may compromise the tissue bioenergetic efficiency inducing cellular dysfunction and death (29). The role of mitochondria in cell death pathways is broadly acknowledged. A fundamental step in the mitochondrial apoptotic pathway is induction of a mitochondrial permeability transition, with collapse of the transmembrane electrochemical gradient for hydrogen ions stopping the process of oxidative phosphorylation and efflux of cytochrome c from the intermembrane space into the cytosol. There, cytochrome c combines with apoptotic protease activation factor 1 and ATP to form a complex that activates procaspase 9. Subsequent procaspase 3 recruitment forms an “apoptosome” and activates caspase 3. This complex leads to the activation of nucleases that complete the “intrinsic” or mitochondrial-dependent pathway. There is also an “extrinsic” pathway that can initiate caspase activation and apoptosis without involvement of mitochondrial (49).
In neuroinflammatory conditions such as SAE, cell death may occur by apoptosis or by necrosis due to hypoxia, oxidative stress, and other cytotoxic factors (5). Brain imaging studies of septic patients with septic encephalopathy observed sites of tissue ischemia in the brain and lesions predominately in the white matter, suggesting increased BBB permeability, which were associated with poor outcome (50, 51). High levels of NO can induce cell death by two different ways: (i) energy depletion–mediated necrosis and (ii) oxidative/nitrosative stress–mediated apoptosis.
Apoptosis of brain cells occurs after systemic LPS administration, and the hippocampus is the most vulnerable region (52). Inhibition of iNOS reduced the number of apoptotic cells in different brain regions, especially hippocampus, after systemic LPS administration (52). In humans, vascular expression of iNOS also correlated (Spearman τ = 0.57) with neuronal apoptosis in autonomic centers (30) and in hippocampus (53). In this study, Polito et al. observed that neuronal apoptosis is associated with endothelial iNOS expression in humans (53).
Necrotic cell death may be initiated by oxidative damage to DNA and activation of the nuclear DNA-repair enzyme poly(ADP-ribose) polymerase 1 (PARP). Activation of PARP-1 contributes to cell necrosis and organ failure in various inflammatory diseases. Overactivation of PARP-1 dramatically lowers the intracellular concentration of its substrate nicotinamide adenine dinucleotide, creating a bioenergetics imbalance that culminates with ATP depletion and necrotic cell death (54). Poly(ADP-ribose) polymerase 1 inhibition is associated with increased resistance to acute septic peritonitis (55). Nitric oxide can be a mediator of PARP-1 activation, and this pathway seems to be an important mechanism of bioenergetics failure in sepsis (56).
Some effects of NO could be associated to glutamate excitotoxicity (57). Nitric oxide–induced excitotoxicity can be associated with alterations in the metabolism of ascorbate, because intracellular ascorbate depletion increases NOS induction followed by inhibition of glutamate uptake (58). These data are reinforced by the fact that CSF ascorbate levels are lower in septic patients, and this correlated with the severity of neurologic symptoms (41). Furthermore, administration of an N-methyl-D-aspartate ionotropic glutamate receptor antagonist prevents the destruction of cholinergic neurons caused by LPS in a chronic inflammation model (59).
Alterations on the BBB permeability
The interface between the CNS and the circulatory system (blood or CSF) is the BBB. The BBB ensures the homeostasis of the microenvironment of the brain parenchyma, regulating ionic balance, managing the transport of nutrients, and preventing the entry of potentially harmful molecules in the system (60). Its structure is dynamic and composed of different cell types, including endothelial cells, the pericytes, astrocytes, microglia, and neurons. The interaction between these cells regulates critical events for the CNS function, such as the permeability of the BBB, cerebral blood flow, and synaptic activity. The endothelial cells of the BBB are maintained together by complex structures, called occlusive junctions (tight junctions). These junctions are formed and maintained by transmembrane proteins (claudin and occludin) connected to cytoskeletal via its cytoplasmic domain.
One major component of systemic inflammation and sepsis is the increase in vascular permeability and edema formation. Recently, we demonstrated by magnetic resonance imaging (MRI) studies that experimental sepsis (CLP) affected brain by distinct mechanisms resulting in cytotoxic and vasogenic edema, as well as in neuronal damage (61). Sharshar and colleges (51) studied by MRI a series of septic patients and identified the presence of leukoencephalopathy surrounding Virchow-Robin spaces, suggesting BBB breakdown in this cases (51).
Compromised barrier integrity has been evidenced in animal models and human sepsis by monitoring the levels or transport of various markers in the brain parenchyma (5, 62). Other studies support the concept that systemic infection can induce an increased production of oxidizing species, tissue damage products, and release of endogenous molecules such as cytokines, complement, or heme, which have the potential to modify the proteins of the endothelial junctions, thus altering the permeability of the BBB. In vitro studies with mouse cerebrovascular endothelial cells challenged with septic plasma demonstrated tight junction instability and increased permeability due to production of ROS and NO (63). Matrix metalloproteinases (MMPs) have been imputed to have a role in several neuronal diseases. The MMPs are molecules involved in tissue injury and repair, and its activity can be induced by cytokines and oxidative stress, resulting in degradation of basal lamina surrounding BBB. Woo et al (64) showed intimate cross-talk between MMPs and ROS, where targeting ROS with inhibitors suppressed the expression and production of MMP-3 and MMP-9, NO, and tumor necrosis factor α, suggesting a possible role of ROS in MMP expression as well as proinflammatory cytokine expression.
There are evidences both from animal models and humans that survivors from sepsis presented long-term cognitive impairment (2, 65). These alterations could be, at least in part, secondary to oxidative stress. Survivors from sepsis presented oxidative damage markers in some brain regions (40), and decreased brain oxidative damage is associated with therapeutic interventions that prevent cognitive impairment (66).
The most convincing evidence linking oxidative damage and long-term cognitive impairment comes from animal studies. Barichello et al. (67) demonstrated that the administration of N-acetyl-cysteine plus deferoxamine in the acute phase of CLP model was able to prevent long-term oxidative damage. This protective effect is robust because it is evident in several different paradigms of cognitive assessment such as the inhibitory avoidance, the open-field task, and the continuous multiple-trials step-down inhibitory avoidance task. This effect is associated with a decrease in brain oxidative damage parameters observed in the early stages of sepsis development, linking early oxidative damage to long-term cognitive impairment.
Mechanisms of long-term cognitive decline
There are two hypotheses of long-term cognitive decline: the neurodegenerative, involving microglial activation, and the vascular, related to diffuse ischemic damage. Both are not exclusive and deserved to be addressed. Indeed, microglial activation has been suggested to be a key mechanism of delirium progress toward cognitive decline (68). This hypothesis is supported by microglial incrimination in neurodegenerative disorders, especially Alzheimer dementia (69). In addition, Weberpals et al. (70) reported that cognitive impairment in endotoxemic mice was associated with activation of glial cells and not neuronal death; Semmler et al. (71) showed septic rats that developed cognitive dysfunction have a reduced cholinergic innervation. According to this hypothesis, the decrease in cholinergic inhibition of the microglial cells would make them neurotoxic (72). However, this hypothesis has been partly refuted by a clinical trial on rivastigmine showing no benefit in terms of prevention of postoperative delirium (73).
It has been recently shown that elevated level of amyloid β in intensive care patients with delirium is correlated with long-term cognitive impairment (74). Neuropathological and neuroradiological reports support the ischemic process. Maybe a thorough and regular assessment of cognitive function would help to discriminate the role of the two main hypotheses (vascular and neurodegenerative). In addition to these mechanisms, insults of axons might be involved. Indeed, one may argue that white matter lesions observed on MRI can partly be due to an axonopathy. Interestingly, a preliminary neuroradiological study suggests that white matter lesions induced by sepsis are associated with cognitive decline (75). Finally, it seems that insults of hippocampus would account for the pattern of long-term psychological disorders and cognitive dysfunction (40, 66, 71). Indeed, hippocampus is involved in posttraumatic stress disorder pathophysiology as well as in attention and memory, which are the two functions the most frequently altered. As aforementioned, it has been shown that reduction of oxidative stress in hippocampus is associated with less cognitive dysfunction in septic rats (67). Other structures can be involved, notably cholinergic innervation of parietal cortex (71). Once again, iNOS seems to be involved as NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits (70).
There is a large body of evidence supporting the occurrence of oxidative stress, bioenergetics, and mitochondrial dysfunctions in the brain during sepsis. The relationship between these alterations and the cognitive dysfunction is less clear, despite the fact that some information is available in this context. The translation of this experimental knowledge into changes in clinical practice will need novel findings both from animal models and humans.
BBB: blood-brain barrier
GLUT: glucose transporter
iNOS: inducible nitric oxide synthase
MMP: matrix metalloproteinase
NADPH: nicotinamide adenine dinucleotide phosphate
NOX: NADPH oxidase
NO: nitric oxide
PARP-1: poly(ADP-ribose) polymerase 1
ROS: reactive oxygen species
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Sepsis; infection; central nervous system; microglia; neuroinflammation; mitochondrial; energy
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