Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.
Altered mitochondrial energy metabolism contributes to the pathophysiology of acute brain injury caused by ischemia, trauma, and neurotoxins and by chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Although much evidence supports that the electron transport chain dysfunction in these metabolic abnormalities has both genetic and intracellular environmental causes, alternative mechanisms are being explored. These include direct, reversible inhibition of cytochrome oxidase by nitric oxide, release of mitochondrial cytochrome c, oxidative inhibition of mitochondrial matrix dehydrogenases and adenine nucleotide transport, the availability of NAD for dehydrogenase reactions, respiratory uncoupling by activities such as that of the permeability transition pore, and altered mitochondrial structure and intracellular trafficking. This review focuses on the catabolism of neuronal NAD and the release of neuronal mitochondrial NAD as important contributors to metabolic dysfunction. In addition, the relationship between apoptotic signaling cascades and disruption of mitochondrial energy metabolism is considered in light of the fine balance between apoptotic and necrotic neural cell death.
PARP-1; nitric oxide; calcium; apoptosis; mitochondrial permeability transition
Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, sepsis and aging. These processes may be favorably affected by melatonin through its radical scavenging properties and/or antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in keratinocytes, the main cell population of the skin where it would contribute to protection against damage induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR-induced apoptosis in cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases-dependent apoptotic pathways and involvement of poly(ADP-ribose) polymerase (PARP) activation as well as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm2), melatonin treated, cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less nuclear condensation as compared to irradiated, nonmelatonin-treated controls. Preincubation with melatonin also led to normalization of the decreased UVR-induced mitochondrial membrane potential. These melatonin effects were followed by suppression of the activation of mitochondrial pathway-related initiator caspase 9 (casp-9), but not of death receptor-dependent casp-8 between 24 and 48 hr after UVR exposure. Melatonin down-regulated effector caspases (casp-3/casp-7) at 24–48 hr post-UV irradiation and reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV-irradiated keratinocytes maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes.
antioxidant; apoptosis; caspases; keratinocytes; melatonin; mitochondria; poly(ADP-ribose) polymerase; ultraviolet radiation
Mitochondrial dysfunction occurs in neurodegenerative diseases, however molecular mechanisms underlying this process remain elusive. Emerging evidence suggests that nitrosative stress, mediated by reactive nitrogen species (RNS), may play a role in mitochondrial pathology. Here, we review findings that highlight the abnormal mitochondrial morphology observed in many neurode-generative disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. One mechanism whereby RNS can affect mitochondrial function and thus neuronal survival occurs via protein S-nitrosylation, representing chemical reaction of a nitric oxide (NO) group with a critical cysteine thiol. In this review, we focus on the signaling pathway whereby S-nitrosylation of the mitochondrial fission protein Drp1 (dynamin-related protein 1; forming S-nitrosothiol (SNO)-Drp1) precipitates excessive mitochondrial fission or fragmentation and consequent bioenergetic compromise. Subsequently, the formation of SNO-Drp1 leads to synaptic damage and neuronal death. Thus, intervention in the SNO-Drp1 pathway may provide therapeutic benefit in neurodegenerative diseases.
S-nitrosothiol; neurodegeneration; dendritic spine loss; GTPase; reactive nitrogen species; mitochondrial dysfunction
Neuronal oxidative stress and mitochondrial dysfunction have been implicated in Parkinson’s disease. Melatonin is a natural antioxidant and free radical scavenger that has been shown to effectively reduce cellular oxidative stress and protect mitochondrial functions in vitro. However, whether melatonin is capable of slowing down the neurodegenerative process in animal models of Parkinson’s disease remains controversial. In this research, we examined long-term melatonin treatment on striatal mitochondrial and dopaminergic functions and on animal locomotor performance in a chronic mouse model of Parkinson’s disease originally established in our laboratory by gradually treating C57BL/6 mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (15 mg/kg, s.c.) and probenecid (250 mg/kg, i.p.) over five weeks. We report here that when the chronic Parkinsonian mice were pre-treated and continuously treated with melatonin (5 mg/kg/day, i.p.) for 18 weeks, the defects of mitochondrial respiration, ATP and antioxidant enzyme levels detected in the striatum of chronic Parkinson’s mice were fully preempted. Meanwhile, the striatal dopaminergic and locomotor deficits seen in the chronic Parkinson’s mice were partially and significantly forestalled. These results imply that long-term melatonin is not only mitochondrial protective but also moderately neuronal protective in the chronic Parkinson’s mice. Melatonin may potentially be effective for slowing down the progression of idiopathic Parkinson’s disease and for reducing oxidative stress and respiratory chain inhibition in other mitochondrial disorders.
Parkinson’s disease; chronic MPTP/probenecid model; neurodegeneration; neuroprotection; mitochondrial dysfunction
Melatonin is an endogenous indoleamine present in different tissues, cellular compartments and organelles including mitochondria. When melatonin is administered orally, it is readily available to the brain where it counteracts different processes that occur during aging and age-related neurodegenerative disorders. These aging processes include oxidative stress and oxidative damage, chronic and acute inflammation, mitochondrial dysfunction and loss of neural regeneration. This review summarizes age related changes in the brain and the importance of oxidative/nitrosative stress and mitochondrial dysfunction in brain aging. The data and mechanisms of action of melatonin in relation to aging of the brain are reviewed as well.
Melatonin; mitochondria; oxidative stress; brain; aging; neurodegenerative diseases; neural stem cells.
By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders - Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.
Neurons are known to use large amounts of energy for their normal function and activity. In order to meet this demand, mitochondrial fission, fusion, and movement events (mitochondrial dynamics) control mitochondrial morphology, facilitating biogenesis and proper distribution of mitochondria within neurons. In contrast, dysfunction in mitochondrial dynamics results in reduced cell bioenergetics and thus contributes to neuronal injury and death in many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease. We recently reported that amyloid-β peptide, thought to be a key mediator of AD pathogenesis, engenders S-nitrosylation and thus hyperactivation of the mitochondrial fission protein Drp1. This activation leads to excessive mitochondrial fragmentation, bioenergetic compromise, and synaptic damage in models of AD. Here, we provide an extended commentary on our findings of nitric oxide-mediated abnormal mitochondrial dynamics.
S-Nitrosylation; Dynamin-related protein 1; Alzheimers’s disease; Mitochondrial fission
Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca2+ overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O2 and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca2+-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.
biogenesis; mitophagy; Nrf2; oxidative stress; peroxisome proliferator-activated receptor-gamma coactivator 1a; protein kinase C
The loss or injury of neurons associated with oxidative and nitrosative redox stress plays an important role in the onset of various neurodegenerative diseases. Specifically, nitric oxide (NO), can affect neuronal survival through a process called S-nitrosylation, by which the NO group undergoes a redox reaction with specific protein thiols. This in turn can lead to the accumulation of misfolded proteins, which generally form aggregates in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Evidence suggests that S-nitrosylation can also impair mitochondrial function and lead to excessive fission of mitochondria and consequent bioenergetic compromise via effects on the activity of the fission protein dynamin-related protein 1 (Drp1). This insult leads to synaptic dysfunction and loss. Additionally, high levels of NO can S-nitrosylate a number of aberrant targets involved in neuronal survival pathways, including the antiapoptotic protein XIAP, inhibiting its ability to prevent apoptosis.
Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases.
Abnormal mitochondrial dynamics; Aging; Alzheimer’s disease; Huntington’s disease; Mitochondria; Mitochondria-targeted antioxidants; Neurodegenerative Disease; Parkinson’s disease
Alzheimer’s disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid.
Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance.
Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The “healthy cell bias of estrogen action” hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.
Melatonin, the hormone of darkness and messenger of the photoperiod, is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone’s intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo, and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis, hemorrhagic shock, ischemia/reperfusion, and in numerous models of toxic liver injury. Melatonin’s influence on hepatic antioxidant enzymes and other potentially relevant pathways, such as nitric oxide signaling, hepatic cytokine and heat shock protein expression, are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection, this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.
Antioxidant enzymes; Hemorrhagic shock; Hepatoprotection; Ischemia; Liver; Liver function; Melatonin; Melatonin receptor; Ramelteon; Reperfusion; Sepsis; Toxic liver injury
Many age-associated disorders (including diabetes, cancer, and
neurodegenerative diseases) are linked to mitochondrial dysfunction, which
leads to impaired cellular bioenergetics and increased oxidative stress.
However, it is not known what genetic and molecular pathways underlie
differential vulnerability to mitochondrial dysfunction observed among
different cell types.
Starting with an insulinoma cell line as a model for a neuronal/endocrine
cell type, we isolated a novel subclonal line (named CRI-G1-RS) that was
more susceptible to cell death induced by mitochondrial respiratory chain
inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity).
Compared to parental RR cells, RS cells were also more vulnerable to direct
oxidative stress, but equally vulnerable to mitochondrial uncoupling and
less vulnerable to protein kinase inhibition-induced apoptosis. Thus,
differential vulnerability to mitochondrial toxins between these two cell
types likely reflects differences in their ability to handle metabolically
generated reactive oxygen species rather than differences in ATP
production/utilization or in downstream apoptotic machinery. Genome-wide
gene expression analysis and follow-up biochemical studies revealed that, in
this experimental system, increased vulnerability to mitochondrial and
oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1
antioxidant pathway; (2) decreased expression of antioxidant and phase I/II
conjugation enzymes, most of which are Nrf2 transcriptional targets; (3)
increased expression of molecular chaperones, many of which are also
considered Nrf2 transcriptional targets; (4) increased expression of β
cell-specific genes and transcription factors that specify/maintain β
cell fate; and (5) reconstitution of glucose-stimulated insulin
The molecular profile presented here will enable identification of individual
genes or gene clusters that shape vulnerability to mitochondrial dysfunction
and thus represent potential therapeutic targets for diabetes and
neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell
line represents a new experimental model for investigating how endogenous
antioxidants affect glucose sensing and insulin release by pancreatic β
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder with unknown etiology. It is marked by widespread neurodegeneration in the brain with profound loss of A9 midbrain dopaminergic neurons in substantia nigra pars compacta. Several theories of biochemical abnormalities have been linked to pathogenesis of PD of which mitochondrial dysfunction due to an impairment of mitochondrial complex I and subsequent oxidative stress seems to take the center stage in experimental models of PD and in postmortem tissues of sporadic forms of illness. Recent identification of specific gene mutations and their influence on mitochondrial functions has further reinforced the relevance of mitochondrial abnormalities in disease pathogenesis. In both sporadic and familial forms of PD abnormal mitochondrial paradigms associated with disease include impaired functioning of the mitochondrial electron transport chain, aging associated damage to mitochondrial DNA, impaired calcium buffering, and anomalies in mitochondrial morphology and dynamics. Here we provide an overview of specific mitochondrial functions affected in sporadic and familial PD that play a role in disease pathogenesis. We propose to utilize these gained insights to further streamline and focus the research to better understand mitochondria's role in disease development and exploit potential mitochondrial targets for therapeutic interventions in PD pathogenesis.
Mitochondrial dysfunction; Mitochondrial DNA; Electron transport chain; Permeability transition pore; α-synuclein; Parkin; PINK1; DJ-1; LRRK2
Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage.
Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines.
MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001).
Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.
co-enzyme Q10; interleukin-6; interleukin-10; melatonin; sepsis; tocopherol
Sleep disorders constitute major nonmotor features of Parkinson’s disease (PD) that have a substantial effect on patients’ quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT1 and MT2 receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed.
agomelatine; insomnia; light therapy; melatonin; oxidative stress; Parkinson’s disease; ramelteon; REM sleep behavior disorder; tasimelteon
The pathological processes of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases engender synaptic and neuronal cell damage. While mild oxidative and nitrosative (nitric oxide (NO)-related) stress mediates normal neuronal signaling, excessive accumulation of these free radicals is linked to neuronal cell injury or death. In neurons, N-methyl--aspartate (NMDA) receptor (NMDAR) activation and subsequent Ca2+ influx can induce the generation of NO via neuronal NO synthase. Emerging evidence has demonstrated that S-nitrosylation, representing covalent reaction of an NO group with a critical protein thiol, mediates the vast majority of NO signaling. Analogous to phosphorylation and other posttranslational modifications, S-nitrosylation can regulate the biological activity of many proteins. Here, we discuss recent studies that implicate neuropathogenic roles of S-nitrosylation in protein misfolding, mitochondrial dysfunction, synaptic injury, and eventual neuronal loss. Among a growing number of S-nitrosylated proteins that contribute to disease pathogenesis, in this review we focus on S-nitrosylated protein-disulfide isomerase (forming SNO-PDI) and dynamin-related protein 1 (forming SNO-Drp1). Furthermore, we describe drugs, such as memantine and newer derivatives of this compound that can prevent both hyperactivation of extrasynaptic NMDARs as well as downstream pathways that lead to nitrosative stress, synaptic damage, and neuronal loss.
NMDA receptor; S-nitrosylation; misfolded protein; mitochondrial dysfunction; neurodegeneration
Mitochondrial dysfunction is a key pathologic event in cardiac ischemia-reperfusion (IR) injury, and protection of mitochondrial function is a potential mechanism underlying ischemic preconditioning (IPC). Acknowledging the role of nitric oxide (NO•) in IPC, it was hypothesized that mitochondrial protein S-nitrosation may be a cardioprotective mechanism. The reagent S-nitroso-2-mercaptopropionyl-glycine (SNO-MPG) was therefore developed to enhance mitochondrial S-nitrosation and elicit cardioprotection. Within cardiomyocytes, mitochondrial proteins were effectively S-nitrosated by SNO-MPG. Consistent with the recent discovery of mitochondrial complex I as an S-nitrosation target, SNO-MPG inhibited complex I activity and cardiomyocyte respiration. The latter effect was insensitive to the NO• scavenger c-PTIO, indicating no role for NO•-mediated complex IV inhibition. A cardioprotective role for reversible complex I inhibition has been proposed, and consistent with this SNO-MPG protected cardiomyocytes from simulated IR injury. Further supporting a cardioprotective role for endogenous mitochondrial S-nitrosothiols, patterns of protein S-nitrosation were similar in mitochondria isolated from Langendorff perfused hearts subjected to IPC, and mitochondria or cells treated with SNO-MPG. The functional recovery of perfused hearts from IR injury was also improved under conditions which stabilized endogenous S-nitrosothiols (i.e. dark), or by pre-ischemic administration of SNO-MPG. Mitochondria isolated from SNO-MPG-treated hearts at the end of ischemia exhibited improved Ca2+ handling and lower ROS generation. Overall these data suggest that mitochondrial S-nitrosation and complex I inhibition constitute a protective signaling pathway that is amenable to pharmacologic augmentation.
Experimental Therapeutics; NO donor; S-nitrosothiol; Complex I; Preconditioning; MPG
The etiology of neurodegenerative disorders like Parkinson’s disease remains unknown, although many genetic and environmental factors are suggested as likely causes. Neuronal oxidative stress and mitochondrial dysfunction have been implicated as possible triggers for the onset and progression of Parkinson’s neurodegeneration. We have recently shown that long-term treadmill exercise prevented neurological, mitochondrial and locomotor deficits in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid-induced mouse model of Parkinson’s disease that was originally established in our laboratory. In the present study, we further demonstrated that long-term exercise attenuated both cytochrome c release and elevated levels of p53, which are known to be associated with mitochondrial dysfunction in the striatum of this chronic model. On the other hand, the expressions of mitochondrial transcription factor A and peroxisome proliferator-activated receptor gamma coactivator 1α were unexpectedly upregulated in the striatum of this chronic model, but long-term exercise training brought their levels down closer to normal. Our findings suggest that maintaining normal mitochondrial function is essential for preventing the process of Parkinson’s disease-like neurodegeneration, whereas stimulating the mitochondrial transcription factors for biogenesis is not obligatory.
chronic MPTP model; cytochrome c; mitochondrial DNA defect; neurodegeneration; p53; Parkinson’s disease; PGC-1α; TFAM; treadmill exercise
Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction (AMI). However reperfusion is responsible for additional myocardial damage, which likely involves opening of the mitochondrial permeability transition pore (mPTP). In reperfusion injury, mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability. Major mechanisms of mitochondrial dysfunction include the long lasting opening of mPTPs and the oxidative stress resulting from formation of reactive oxygen species (ROS). Several signaling cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning, obtained with brief intermittent ischemia or with pharmacological agents. These pathways converge on a common target, the mitochondria, to preserve their function after ischemia/reperfusion. The present review discusses the role of mitochondria in cardioprotection, especially the involvement of adenosine triphosphate-dependent potassium channels, ROS signaling, and the mPTP. Ischemic postconditioning has emerged as a new way to target the mitochondria, and to drastically reduce lethal reperfusion injury. Several clinical studies using ischemic postconditioning during angioplasty now support its protective effects, and an interesting alternative is pharmacological postconditioning. In fact ischemic postconditioning and the mPTP desensitizer, cyclosporine A, have been shown to induce comparable protection in AMI patients.
Adenosine triphosphate-dependent potassium channels; Cardioprotection; Ischemia-reperfusion injury; Mitochondrial permeability transition pore; Reactive oxygen species
Ischemia/reperfusion (IR) injury is a central component in the pathogenesis of several diseases and is a leading cause of morbidity and mortality in the western world. Subcellularly, mitochondrial dysfunction, characterized by depletion of ATP, calcium-induced opening of the mitochondrial permeability transition pore, and exacerbated reactive oxygen species (ROS) formation, plays an integral role in the progression of IR injury. Nitric oxide (NO) and more recently nitrite (NO2-) are known to modulate mitochondrial function, mediate cytoprotection after IR and have been implicated in the signaling of the highly protective ischemic preconditioning (IPC) program. Here, we review what is known about the role of NO and nitrite in cytoprotection after IR and consider the putative role of nitrite in IPC. Focus is placed on the potential cytoprotective mechanisms involving NO and nitrite-dependent modulation of mitochondrial function.
A common process associated with oxidative stress and severe mitochondrial impairment is the opening of the mitochondrial permeability transition pore, as described in many neurodegenerative diseases. Thus, inhibition of mitochondrial permeability transition pore opening represents a potential target for inhibiting mitochondrial-driven cell death. Among the mitochondrial permeability transition pore components, cyclophilin D is the most studied and has been found increased under pathological conditions. Here, we have used in vitro and in vivo models of X-linked adrenoleukodystrophy to investigate the relationship between the mitochondrial permeability transition pore opening and redox homeostasis. X-linked adrenoleukodystrophy is a neurodegenerative condition caused by loss of function of the peroxisomal ABCD1 transporter, in which oxidative stress plays a pivotal role. In this study, we provide evidence of impaired mitochondrial metabolism in a peroxisomal disease, as fibroblasts in patients with X-linked adrenoleukodystrophy cannot survive when forced to rely on mitochondrial energy production, i.e. on incubation in galactose. Oxidative stress induced under galactose conditions leads to mitochondrial damage in the form of mitochondrial inner membrane potential dissipation, ATP drop and necrotic cell death, together with increased levels of oxidative modifications in cyclophilin D protein. Moreover, we show increased expression levels of cyclophilin D in the affected zones of brains in patients with adrenomyeloneuropathy, in spinal cord of a mouse model of X-linked adrenoleukodystrophy (Abcd1-null mice) and in fibroblasts from patients with X-linked adrenoleukodystrophy. Notably, treatment with antioxidants rescues mitochondrial damage markers in fibroblasts from patients with X-linked adrenoleukodystrophy, including cyclophilin D oxidative modifications, and reverses cyclophilin D induction in vitro and in vivo. These findings provide mechanistic insight into the beneficial effects of antioxidants in neurodegenerative and non-neurodegenerative cyclophilin D-dependent disorders.
Cyclophilin D; mitochondrial permeability transition pore; neurodegenerative disease; oxidative stress; X-linked adrenoleukodystrophy
Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.
Bcl-2; lithium; methamphetamine; mitochondria; valproate
Excessive nitrosative and oxidative stress is thought to trigger cellular signaling pathways leading to neurodegenerative conditions. Such redox dysregulation can result from many cellular events, including hyperactivation of the N-methyl-d-aspartate-type glutamate receptor, mitochondrial dysfunction, and cellular aging. Recently, we and our colleagues have shown that excessive generation of free radicals and related molecules, in particular nitric oxide species (NO), can trigger pathological production of misfolded proteins, abnormal mitochondrial dynamics (comprised of mitochondrial fission and fusion events), and apoptotic pathways in neuronal cells. Emerging evidence suggests that excessive NO production can contribute to these pathological processes, specifically by S-nitrosylation of specific target proteins. Here, we highlight examples of S-nitrosylated proteins that regulate misfolded protein accumulation and mitochondrial dynamics. For instance, in models of Parkinson's disease, these S-nitrosylation targets include parkin, a ubiquitin E3 ligase and neuroprotective molecule, and protein-disulfide isomerase, a chaperone enzyme for nascent protein folding. S-Nitrosylation of protein-disulfide isomerase may also be associated with mutant Cu/Zn superoxide dismutase toxicity in amyotrophic lateral sclerosis. Additionally, in models of Alzheimer's disease, excessive NO generation leads to the formation of S-nitrosylated dynamin-related protein 1 (forming SNO-Drp1), which contributes to abnormal mitochondrial fragmentation and resultant synaptic damage. Antioxid. Redox Signal. 14, 1479–1492.