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At least 739 records · Page 41Linked to original sources
PubMed2003

Mitochondria respiration and susceptibility to ischemia-reperfusion injury in diabetic hearts.

Cardiovascular complications are the primary cause of death for diabetic patients. Clinical and experimental observation has showed the development of dysfunctional cardiomyopathy as one of the main complications of diabetes. Whether the cardiomyopathy results from an increased susceptibility of cardiac tissue to ischemic insult or from a specific functional defect of cardiac mitochondria is a controversial issue. The investigation of possible functional defect in cardiac mitochondria from diabetic rats indicates a decline in state 3 respiration only in animals presenting a marked decrease in body weight. Mitochondria from rats presenting a level of hyperglycemia similar to diabetic animals but not the marked weight loss typical of the latter group show no decline in state 3 respiration, the values being indistinguishable from those of control mitochondria. Mitochondria from hyperglycemic rats, however, show a 15-20% increase in state 4 oxygen consumption but only when glutamate is used as energetic substrate, as compared to a 40-50% increase in state 4 respiration in mitochondria from diabetic rats under similar experimental conditions. This phenomenon is unrelated to diabetes duration, as it is observed at 2 as well as 8 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats and indicate that differences exist in cardiac mitochondrial function in rats generically labeled as diabetic. These differences can contribute to explain discrepancies in experimental results reported by various groups in the field and provide an additional parameter to be taken into consideration in evaluating the varying sensitivity of diabetic hearts to ischemia-reperfusion injury.

Animals↗
PubMed2006

Proteomic analysis of cellular change involved in mitochondria-to-nucleus communication in L6 GLUT4myc myocytes.

Genetic or biochemical abnormalities in mitochondria are closely associated with apoptosis, aging, cancer, and other chronic degenerative diseases. Mitochondrial dysfunction resulting from mitochondrial DNA (mtDNA) depletion dispatches retrograde signals to the nucleus to compensate by altering the expression of various genes. In this study, a proteomic approach was used to gain insight into the nuclear gene targets of mitochondrial stress signaling and the pathophysiological mechanisms associated with mitochondrial dysfunction. We have used 2-DE to characterize the nuclear gene responses resulting from mtDNA depletion in L6 GLUT4myc myocytes. Our results showed that 77 polypeptides were differentially expressed in mtDNA-depleted cells; 33 polypeptides were down-regulated and 44 polypeptides were up-regulated. Of these differentially expressed polypeptides, 40 were identified as 36 different proteins by MALDI-TOF MS. These proteins are related to various cellular responses, such as apoptosis, cellular metabolism, signaling and cytoskeleton functions. It is suggested that the insulin resistance developed in mtDNA-depleted myocytes may be associated with disorganization of cytoskeleton assembly, and that cellular mtDNA depletion might promote the ability to evade apoptosis or other death effectors.

Animals↗
PubMed1996

Detoxification of reactive aldehydes in mitochondria: effects of age and dietary restriction.

Previously, we proposed that reactive aldehydic products generated from lipid peroxidation might be the deleterious cause of mitochondrial dysfunction during aging. Our present study focuses on the roles that aging and dietary restriction (DR) play in the elimination of 4-hydroxynonenal (HNE) in rat liver by exploring three enzymatic systems: aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), and alcohol dehydrogenase (ADH). Results show that the main pathways of HNE elimination in mitochondria are through ALDH-catalyzed oxidation, and the GST-catalyzed conjugation of HNE. Findings also show that age reduces both ALDH and GST activities; mitochondrial HNE oxidation by ALDH declines at 18 and 24 months of age, and the glutathione conjugation of HNE reduces at 24 months of age. However, these enzymatic processes were found to be well-preserved in DR animals throughout their life span, supporting the evidence of less HNE accumulation in the membranes of restricted rats. These findings are consistent with our earlier proposal that indicates an age-associated decrease in mitochondrial detoxification as a major underlying process for malondialdehyde and lipofuscin accumulation in older animals. They also indicate that the prevention of the age-associated decrease in aldehyde detoxification by DR may be an important mechanism underlying enhanced aldehyde elimination, thus minimizing the functional deterioration observed in mitochondria of old animals.

Aging↗
PubMed2025

Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration.

Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD+/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD+/NADH imbalance. Niacin restored the NAD+/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.

Humans↗
PubMed2005

Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury.

Mitochondrial oxidative damage contributes to a wide range of pathologies, including cardiovascular disorders and neurodegenerative diseases. Therefore, protecting mitochondria from oxidative damage should be an effective therapeutic strategy. However, conventional antioxidants have limited efficacy due to the difficulty of delivering them to mitochondria in situ. To overcome this problem, we developed mitochondria-targeted antioxidants, typified by MitoQ, which comprises a lipophilic triphenylphosphonium (TPP) cation covalently attached to a ubiquinol antioxidant. Driven by the large mitochondrial membrane potential, the TPP cation concentrates MitoQ several hundred-fold within mitochondria, selectively preventing mitochondrial oxidative damage. To test whether MitoQ was active in vivo, we chose a clinically relevant form of mitochondrial oxidative damage: cardiac ischemia-reperfusion injury. Feeding MitoQ to rats significantly decreased heart dysfunction, cell death, and mitochondrial damage after ischemia-reperfusion. This protection was due to the antioxidant activity of MitoQ within mitochondria, as an untargeted antioxidant was ineffective and accumulation of the TPP cation alone gave no protection. Therefore, targeting antioxidants to mitochondria in vivo is a promising new therapeutic strategy in the wide range of human diseases such as Parkinson's disease, diabetes, and Friedreich's ataxia where mitochondrial oxidative damage underlies the pathology.

Animals↗
PubMed2005

Cyclical mitochondrial deltapsiM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca+2 exchange are reduced in Alzheimer's disease cybrids.

Reduced complex IV, increased oxidative stress and beta amyloid peptide secretion in Alzheimer's disease (AD) can be replicated in cybrid models. We characterized cyclical mitochondrial deltapsiM fluctuations ('flickering') in neuroblastoma cells and AD/CTL cybrids. Flickering was blocked by ATP-synthase inhibition, was not observed in rho0 cells and was not blocked by antioxidant treatment. Flickering was not affected by the Ca(+2) uniporter antagonist Ru360 but was eliminated by BAPTA or CGP37137 blockade of the mitochondrial Na(+)/Ca(+2) exchanger. AD cybrid mitochondria showed reduced flickering. Flickering seems to represent coupling of deltapsiM to F0F1 ATP-synthase; reduction of flickering in AD cybrids suggests dysfunction of this coupling.

Alzheimer Disease↗
PubMed2003

Heat shock pretreatment prevents cardiac mitochondrial dysfunction during sepsis.

The present study was designed to investigate the effect of previous heat shock treatment on the mitochondria function of the heart during a cecal ligation and puncture (CLP)-induced sepsis model. Rats of the heated group were heated by whole-body hyperthermia 24 h before the CLP operation. Cardiac mitochondria were freshly collected 9 and 18 h after CLP, indicating early and late sepsis, respectively. The expressions of heat shock protein 72 (Hsp72), glucose-regulated protein 75 (Grp75), and mitochondrial complexes I, II, III, and IV were evaluated by Western blot and immunochemical analysis. Enzyme activities of NADH cytochrome c reductase (NCCR), succinate cytochrome c reductase (SCCR), and cytochrome c oxidase (CCO) were measured after the reduction or oxidation of cytochrome c using a spectrophotometer. The results showed that the ATP content in the heart significantly declined during late sepsis, whereas heat shock treatment reversed this declination. The enzyme activities of NCCR, SCCR, and CCO were apparently suppressed during late stage of sepsis. The protein expressions of mitochondrial complex II and complex IV and Grp75 were also down-regulated during sepsis. Previously treated by heat shock, late-sepsis rats emerged with a high preservation of mitochondrial respiratory chain enzymes, both the protein amount and enzyme activity. Aspects of morphology were observed by electron microscopy, while heat shock treatment revealed the attenuation of cardiac mitochondrial damage induced by sepsis. In conclusion, structural deformity and the decrease of respiratory chain enzyme activity in mitochondria and its leading to a decline of ATP content are highly correlated with the deterioration of cardiac function during sepsis, and heat shock can reverse adverse effects, thus achieving a protective goal.

Adenosine Triphosphate↗
PubMed1993

Mitochondrial and glycolytic dysfunction in lethal injury to hepatocytes by t-butylhydroperoxide: protection by fructose, cyclosporin A and trifluoperazine.

In isolated mitochondria, t-butylhydroperoxide (t-BuOOH) and other pro-oxidants cause a permeability transition characterized by increased permeability to small ions, swelling and loss of membrane potential. Cyclosporin A and trifluoperazine inhibit this permeability transition. Here, we investigated the role of the mitochondrial permeability transition in lethal cellular injury from t-BuOOH. Hepatocytes from fasted rats were isolated by collagenase perfusion, and cell viability was assessed by propidium iodide fluorescence. t-BuOOH caused dose- and time-dependent cell killing. Fructose, a substrate for glycolytic ATP formation, protected at lower (< or = 100 microM), but not at higher concentrations of t-BuOOH. In fructose-treated cells, oligomycin (10 micrograms/ml) delayed cell killing after 100 to 300 microM t-BuOOH, whereas cyclosporin A (0.5 microM) plus trifluoperazine (5 microM) even more potently reduced lethal injury. In hepatocyte suspensions, 100 microM t-BuOOH caused mitochondrial depolarization as determined by release of rhodamine 123. Cyclosporin A plus trifluoperazine in the presence of fructose substantially reduced release of rhodamine 123. Similarly, in single cultured hepatocytes viewed by laser scanning confocal microscopy, t-BuOOH caused leakage of rhodamine 123 from mitochondria, an event which preceded cell death and which was delayed by fructose in combination with cyclosporin A plus trifluoperazine. At 1 mM, t-BuOOH inhibited glycolysis, and fructose in combination with either oligomycin or cyclosporin A plus trifluoperazine had only a short-lived protective effect. In conclusion, t-BuOOH toxicity was progressive with increasing dosages. At low t-BuOOH (< or = 50 microM), mitochondrial ATP synthetic capacity was inhibited, but not uncoupled.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2004

Yeast replicative life span--the mitochondrial connection.

Mitochondria have been associated with aging in many experimental systems through the damaging action of reactive oxygen species. There is more, however, to the connection between mitochondria and Saccharomyces cerevisiae longevity and aging. Induction of the retrograde response, a pathway signaling mitochondrial dysfunction, results in the extension of life span and postponement of the manifestations of aging, changing the metabolic and stress resistance status of the cell. A paradox associated with the retrograde response is the simultaneous triggering of extrachromosomal ribosomal DNA circle (ERC) production, because of the deleterious effect these circles have on yeast longevity. The retrograde response gene RTG2 appears to play a pivotal role in ERC production, linking metabolism and genome stability. In addition to mother cell aging, mitochondria are important in establishment of age asymmetry between mother and daughter cells. The results more generally point to the existence of a mechanism to "filter" damaged components from daughter cells, a form of checkpoint control. Mitochondrial integrity is affected by the PHB1 and PHB2 genes, which encode inner mitochondrial membrane chaperones called prohibitins. The Phb1/2 proteins protect the cell from imbalances in the production of mitochondrial proteins. Such imbalances appear to cause a stochastic stratification of the yeast population with the appearance of short-lived cells. Ras2p impacts this process. Maintenance of mitochondrial membrane potential and the provision of Krebs cycle intermediates for biosyntheses appear to be crucial elements in yeast longevity. In sum, it is clear that mitochondria lie at the nexus of yeast longevity and aging.

DNA, Ribosomal↗
PubMed2000

Mitochondria and ageing.

Mitochondria have long been proposed as a perpetrator of aging. We review here the accumulating evidence for chronological alterations in the mitochondrion and discuss how these changes may cause cellular dysfunction and death. We conclude that although the evidence for aging changes in the level of oxidative stress, DNA mutations and biochemical deficiencies in mitochondria are convincing, there is little experimental evidence to link these changes directly with the cellular pathology of aging. Promising avenues for addressing this problem include the investigation of established mitochondrial DNA disorders and the development of animal models with mitochondrial defects.

Aging↗
PubMedDate not supplied

Digitalis cardiotoxicity: cellular calcium overload a possible mechanism.

Isolated perfused guinea pig (Langendorff) heart was employed to determine if the myocardial mechanical dysfunction (mechanical toxicity) produced by toxic concentration of ouabain (1 microM) was accompanied by alterations in mitochondrial function. Ouabain (1 microM) produces a transient increase in the myocardial contractile force and then a continuous decline in the left ventricular mechanical function. Mitochondria isolated from ouabain perfused hearts showed a significantly higher rate of 45Ca2+ uptake and reduction in oxidative phosphorylation. The rate of ATP generation was reduced by almost 50% at the time of contracture development. Verapamil or nifedipine, when combined with ouabain in the perfusion medium, delayed or abolished the mechanical toxicity in a dose dependent manner. The mitochondria isolated from these hearts demonstrated normal rate of Ca2+ uptake and ATP generation capacity. The data indicate that the cardiac mechanical dysfunction induced by toxic doses of ouabain may be associated with mitochondrial Ca2+ overload and dysfunction and that the Ca2+ channel blockers may have a protective effect.

Animals↗
PubMed2005

Drugs targeting mitochondrial functions to control tumor cell growth.

Mitochondria, the power houses of the cell, are at the cross-road of many cellular pathways. They play a central role in energy metabolism, regulate calcium flux and are implicated in apoptosis. Mitochondrial dysfunctions have been associated with various physiopathological disorders, especially neurodegenerative diseases and cancer. Structurally diverse pharmacological agents have shown direct effects on mitochondria ultra-structures and functions, either at the DNA level or upon targeting proteins located in the inner or outer mitochondrial membranes. The brief review deals with the molecular targets and mechanisms of action of chemically diverse small molecules acting on specific mitochondrial loci, such as the respiratory chain, DNA biogenesis, potassium channels, the Bcl-2 protein and the permeability transition pores (PTP). Drugs, which specifically compromise the structural and functional integrity of mitochondria, may provide novel opportunities to combat cancer cell proliferation, providing that these molecules can be selectively delivered to tumor sites. Different examples reported here show that mitochondrial insult or failure can rapidly lead to inhibition of cell survival and proliferation. Mitochondrial impairment may be a successful anti-cancer strategy.

Animals↗
PubMed2002

Effect of oral Tadenan treatment on rabbit bladder structure and function after partial outlet obstruction.

PURPOSE: There is increasing evidence that the progressive dysfunction induced by partial outlet obstruction is mediated by ischemia-reperfusion, and bladder decompensation results from ischemia-reperfusion induced damage to the cellular and subcellular organelle membranes of nerve and smooth muscle, mitochondria and sarcoplasmic reticulum. Tadenan, an extract of Pygeum africanum, is a therapeutic prescribed in Europe to relieve symptoms of obstructive bladder dysfunction secondary to benign prostatic hyperplasia. There is excellent experimental evidence that Tadenan treatment of obstructed rabbits reduces and reverses the progression of bladder decompensation. We determined whether Tadenan therapy can reverse the morphological damage associated with obstructive dysfunction. MATERIAL AND METHODS: A total of 36 male New Zealand White rabbits were separated into 6 groups of 6 each. Rabbits in groups 1 and 2 underwent sham operation. For 3 weeks beginning 2 weeks after sham operation group 1 was treated with vehicle and group 2 was treated with 30 mg./kg. Tadenan daily. Rabbits in groups 3 to 6 underwent partial outlet obstruction surgery. Two weeks after obstruction each rabbit was treated for 3 weeks with vehicle in group 3, and with 1, 10 and 30 mg./kg. Tadenan in groups 4, 5 and 6, respectively. After the completion of treatment cystometry was performed on each rabbit and isolated bladder strips were evaluated for contractile responses to field stimulation, adenosine triphosphate, carbachol and KCl. Separate strips were fixed for electron microscopy to determine the location and severity of cellular and subcellular membrane damage. RESULTS: Partial outlet obstruction resulted in reduced compliance, decreased responses of bladder strips to all forms of stimulation tested, and significant and extensive damage to cellular and subcellular organelle membranes consistent with an ischemia-reperfusion etiology. Daily 1 and 10 mg./kg. Tadenan treatments had little effect on the obstruction induced increase in bladder weight or the deleterious changes in bladder function and structure. However, treating obstructed rabbits with 30 mg./kg. Tadenan daily resulted in reduced bladder hypertrophy, improved compliance, improved contractile responses to nearly normal levels of isolated bladder strips to all stimuli tested and reversal of obstruction induced structural damage to cellular and subcellular organelle membranes. CONCLUSION: Tadenan treatment of obstructed rabbits resulted in a dose dependent improvement in bladder ultrastructure in parallel with improved bladder compliance and contractile responses of isolated strips to stimulation, providing support for the hypothesis that damage to cellular and subcellular organelle membranes mediates the contractile dysfunction induced by partial outlet obstruction.

Animals↗
PubMed1998

Visualization of NMDA receptor-induced mitochondrial calcium accumulation in striatal neurons.

Ca2+ influx through NMDA receptor-gated channels and the subsequent rise in intracellular Ca2+ concentration ([Ca2+]i) have been implicated in cytotoxic processes that lead to irreversible neuronal injury. While many studies have focused on cytosolic Ca2+ homeostasis, much less is known about Ca2+ fluxes in subcellular organelles, such as mitochondria. The mitochondria play an important role in Ca2+ homeostasis by sequestering cytosolic Ca2+ loads. However, mitochondrial Ca2+ overload can impair ATP synthesis, induce free radical formation, and lead to lipid peroxidation. Thus, it is also important to understand the mitochondrial Ca2+ fluxes induced by NMDA. In this study, changes in mitochondrial Ca2+ concentration ([Ca2+]m) in cultured striatal neurons were monitored with a Ca(2+)-binding fluorescent probe, rhod-2, and laser scanning confocal microscopy. The rhod-2 fluorescence signal was highly localized in mitochondrial areas of confocal images. A rapid increase of [Ca2+]m was observed when neurons were treated with 100 microM NMDA. The increased [Ca2+]m induced by NMDA could not be observed in the presence of ruthenium red, an inhibitor of the mitochondrial Ca2+ uniporter, or CCCP, a protonophore that breaks down the mitochondrial membrane potential necessary for Ca2+ uptake. The magnitude and reversibility of changes in [Ca2+]m induced by NMDA were variable. In neurons receiving multiple pulses of NMDA, [Ca2+]m did not return to baseline. The elevated [Ca2+]m may persist indefinitely and may rise further after successive NMDA exposures. These data demonstrate that Ca2+ accumulates in mitochondria in response to NMDA receptor activation. This Ca2+ accumulation may play a role in the excitotoxic mitochondrial dysfunction induced by NMDA.

Animals↗
PubMed2006

Changes in metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy by rapid atrial pacing in dogs.

BACKGROUND: It was the aim of this study to investigate the variation in metalloproteinase and tissue inhibitor of metalloproteinase (TIMP) connexin levels during tachycardia-induced cardiomyopathy (TIC). METHODS: Canine models of TIC were established by rapid right atrial pacing at 350-400 beats per min for 8 weeks in 11 dogs, with another 6 dogs acting as sham operation group. Echocardiography, left ventricular pressure and its first derivation with time (positive and negative maximum, dp/dt(max) and -dp/dt(max)), as well as intracardiac electrograms were recorded before and after rapid pacing at 1, 4 and 8 weeks. Data were acquired in sinus rhythm. Ultrastructural changes in left ventricular tissue were observed by transmission electron microscope. The relative abundance of matrix metalloproteinase (MMP)-9 and TIMP-1 was studied by immunoblotting. RESULTS: The following hemodynamic changes were detected after 8 weeks of rapid pacing: the TIC group had decreased dp/dt(max) (p < 0.05), the left ventricular relaxation time constant (tau) was prolonged (p < 0.05), both left ventricular end-diastolic volume and left ventricular end-systolic volume were decreased (p <0.05), left ventricular end-diastolic pressure was significantly increased (p <0.05), and -dp/dt(max) was significantly decreased (p <0.001) compared with the control group; no statistical differences in the left ventricular ejection fraction between weeks 1, 4 or 8 (p >0.05) were observed, but left ventricular ejection fraction was significantly decreased after 1 week of pacing (p < 0.05). The left ventricular end-diastolic volume was increased after 1 week of pacing compared with the control group (24.15 +/- 8.15 vs.11.19 +/- 4.41 ml; p <0.05), as shown by echocardiography. Compared with the control group, MMP-9 was significantly higher (0.217 +/- 2.16 E-02 vs. 0.314 +/- 5.263 E-02; p < 0.001), while TIMP-1 was decreased (0.230 +/- 8.944 E-02 vs. 0.120 +/- 9.258 E-03; p < 0.001). CONCLUSIONS: Ventricular dilatation and systolic dysfunction occurred after 1 week of rapid right atrial pacing. Enlarged and disarrayed fibers and mitochondria with disintegrated crystal and an anarchic pattern were observed. Additionally, moderate dilation of the rough endoplasmic reticulum and intercalated disk discontinuity were seen after 8 weeks of pacing, and MMP-9 was increased and TIMP-1 was decreased after the same time period.

Animals↗
PubMed1987

The role of calcium in ischemic myocardial injury.

Hypoxia and ischemia produce depression of myocardial contractile function and alterations in calcium homeostasis. Although both functional abnormalities and alterations in calcium handling are reversible under some conditions, reoxygenation or reperfusion can also lead to paradoxical augmentation of injury. Under many conditions of ischemia and reperfusion, however, a causal relation between altered calcium handling and cellular injury has been difficult to establish. Calcium entry through specific calcium channels during and after hypoxic insult can account for only a fraction of the observed pathologic transsarcolemmal calcium flux; sodium-calcium exchange also appears to contribute to calcium influx but to a limited degree. During reoxygenation calcium also appears to enter through nonspecific sarcolemmal permeability changes. The hypothesis that mitochondria are calcium loaded by hypoxia and reoxygenation and that the calcium loading produces mitochondrial dysfunction has not been substantiated convincingly. Brief hypoxia can produce mitochondrial dysfunction without mitochondrial calcium overload, whereas calcium overload per se does not initially produce irreversible cellular injury. Under conditions of prolonged ischemic insult, with or without reperfusion, it is likely that disturbed calcium homeostasis does play a role in ultimate cellular injury. However, available data fall short of establishing intracellular calcium overload as a necessary or sufficient condition to produce irreversible myocardial cell injury.

Animals↗
PubMed2006

The role of mitochondria in inherited neurodegenerative diseases.

In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential 'lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be 'secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases.

Animals↗