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PubMed2005

Adaptive responses to mitochondrial dysfunction in the rho degrees Namalwa cell.

Mitochondrial function depends on the synchronised expression of nuclear and mitochondrial-encoded genes. The expression of many nuclear genes is sensitive to the functional state of mitochondria. Mitochondria containing mutated mtDNA populations have been shown to withstand stress to a high level of tolerance. The prolonged survival of cells that are devoid of mitochondrial DNA is further evidence for the existence of this adaptive response. Yeast cells lacking the mitochondrial genome configure their pattern of nuclear gene expression to accommodate changes in nutrient availability and in response to different stress conditions. Little is known about the signalling pathways that mediate the adaptive response in mammalian cells with mitochondrial dysfunction. To gain a global perspective on adaptive responses in cells with mitochondrial dysfunction, we used Affymetrix microarray technology to compare the whole genome transcription profile of Namalwa cells (rho(+)) to that of a Namalwa cell depleted of mitochondrial DNA (rho degrees ). Our results demonstrate that rho degrees Namalwa induce genes encoding hypoxia target proteins, mitochondrial ribosomal proteins, transport channels, tRNA synthetases and enzymes of the glycolytic pathway and the fatty oxidation pathway suggesting that hypoxia and the ensuing cellular adaptations could play an important adaptive role in cells with mitochondrial dysfunction.

Adaptation, Physiological↗
PubMed2006

Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.

Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and alpha-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I-IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.

Acetyl Coenzyme A↗
PubMed2004

[Changes of thioredoxin mRNA level in neurons with mitochondrial dysfunction insulted by H2O2].

Oxidative stress and mitochondrial deficiency have been considered to be associated with the mechanisms of many neurodegenerative diseases. Sodium azide (NaN3) is a special inhibitor of mitochondrion cytochrome c oxidase (COX), which can be used to mimic neuronal damage induced by mitochondrial deficiency. In this experiment, the neurotoxic effects of H2O2 on primary cultured neurons and NaN3-induced mitochondrial dysfunctional neurons were detected by means of cell viability measurement (MTT) and analyzed through morphological observation. Furthermore, the changes of thioredoxin mRNA level in both normal and abnormal cultured neurons insulted by H2O2 were analyzed by semiquantitative RT-PCR in order to explore the role of Trx, an important redox regulatory protein, in modulating the process of neuronal injury. It was found that mitochondrial dysfunctional neurons could be damaged by H2O2 in a dose- and time-dependent manner and the expression of Trx decreased during certain dose (0-200 mumol/L) and time (0-4 h) of H2O2 treatment. But in normal neurons the effects of H2O2 treatment seemed to be less evident. It suggests that in neurons with mitochondrial dysfunction, the redox modulation of thioredox seems to be more prominent.

Animals↗
PubMed1995

Mitochondrial dysfunction in adult-onset myopathies with structural abnormalities.

Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.

Adult↗
PubMed2006

Mitochondrial genomic contribution to mitochondrial dysfunction in Alzheimer's disease.

Although mitochondrial dysfunction and increased oxidative stress are found in Alzheimer's disease (AD), the origin(s) of the mitochondrial dysfunction, its causal relationship to oxidative stress and the mechanisms of their downstream effects to yield synaptic dysfunction and neuronal death are not known with certainty. The discovery of "classic" mitochondrial diseases where bioenergetic deficiencies were associated with causal mutations or deletions in mitochondrial DNA (mtDNA) generated a search for similar abnormalities in AD samples. At least three-dozen studies since 1992 have failed to find consistent mutational abnormalities in AD mtDNA beyond those associated with aging, with most studies carried out in postmortem brain. Historically, the publication of a new mutation or deletion is followed by other studies that fail to confirm the initial finding. Promising recent findings include heteroplasmic mutations in the D-loop control region. AD brain mtDNA consistently has more oxidative damage beyond that due to aging, providing the potential for generation of mutations/deletions and postgenomic problems with transcriptional regulation. To date no AD brain studies have examined individual neurons to search for clonal expansions of deleted mtDNA's like two recent reports in Parkinson's disease substantia nigra. Cybrid (cytoplasmic hybrid) models, in which mitochondrial DNA (mtDNA) from accessible tissue (platelets) of living AD patients is expressed in replicating human neural cells initially devoid of their own endogenous mtDNA (rho(0) cells) revealed that decreased cytochrome oxidase (CO) activity, increased oxidative stress, increased beta amyloid production, activation of detrimental intracellular signaling and caspases, accelerated mtDNA proliferation, and abnormal mitochondrial morphology and transport can be transmitted through expression of mtDNA from living AD patients. Carrying these cybrid observations into AD brain is necessary to demonstrate any causality of brain mtDNA to contribute to pathogenesis. A novel protein transfection technology that allows transfer of mtDNA into mitochondria of cells ("protofection") will allow this question to be examined. The contribution of altered mtDNA to pathogenesis and progression of AD is suggestive, not proven, and likely very heterogenous.

Alzheimer Disease↗
PubMed2005

Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction.

Diabetic cardiomyopathy is characterized by excessive utilization of fatty acid substrate, diminished glucose transport, and mitochondrial dysfunction. However, the chemical mechanisms linking altered substrate utilization to mitochondrial dysfunction are unknown. Herein, we use shotgun lipidomics and multidimensional mass spectrometry to identify dramatic decreases in the critical mitochondrial inner membrane lipid, cardiolipin, in diabetic murine myocardium (from 7.2 +/- 0.3 nmol/mg of protein in control hearts to 3.1 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Moreover, the direct metabolic precursor of cardiolipin, phosphatidylglycerol, was also substantially depleted (2.5 +/- 0.2 nmol/mg of protein in control hearts vs 1.3 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Similarly, glycerol 3-phosphate, necessary for the penultimate step in phosphatidylglycerol production, decreased by 58% in diabetic myocardium (from 4.9 +/- 0.9 to 2.2 +/- 0.3 nmol/mg of protein; n = 4). Since Barth's syndrome (a disorder of cardiolipin metabolism) induces mitochondrial dysfunction and cardiomyopathy, and since decreases in cardiolipin content precipitate mitochondrial dysfunction, these results provide a unifying hypothesis linking altered substrate utilization and metabolic flux in diabetic myocardium with altered lipid metabolism, cardiolipin depletion, mitochondrial dysfunction, and resultant hemodynamic compromise.

Animals↗
PubMed2006

Vulnerability of neurons with mitochondrial dysfunction to oxidative stress is associated with down-regulation of thioredoxin.

In this study, we first developed an in vitro model of neuron with mitochondrial dysfunction, based on sodium azide (NaN(3))-induced inhibition of cytochrome c oxidase (complex IV) that is reduced in post-mortem AD brains, and then investigated the role of Trx expression in response of neurons with mitochondrial dysfunction to oxidative stress. We found that neurons treated with sub-threshold concentration (8mM) of NaN(3) have mitochondrial dysfunction and that thioredoxin (Trx) mRNA and protein level decreased in neurons with mitochondrial dysfunction though no significant change in the viability. When exposed to extracellular H(2)O(2), neurons with mitochondrial dysfunction were significantly more vulnerable than control neurons. Trx mRNA and protein levels in neurons with mitochondrial dysfunction decreased in a dose- and time-dependent manner (mRNA: 25-150 microM H(2)O(2) for 1h and 50 microM H(2)O(2) for 1-3h; protein: 25-150 microM H(2)O(2) for 1h and 50 microM H(2)O(2) for 1-4h), while those in control neurons had no significant changes (50-250 microM H(2)O(2) for 1h). The data implied that vulnerability of neurons with mitochondrial dysfunction to oxidative stress is associated with down-regulation of thioredoxin.

Animals↗
PubMed2004

Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures.

Mitochondrial dysfunction has been implicated as a contributing factor in diverse acute and chronic neurological disorders. However, its role in the epilepsies has only recently emerged. Animal studies show that epileptic seizures result in free radical production and oxidative damage to cellular proteins, lipids, and DNA. Mitochondria contribute to the majority of seizure-induced free radical production. Seizure-induced mitochondrial superoxide production, consequent inactivation of susceptible iron-sulfur enzymes, e.g., aconitase, and resultant iron-mediated toxicity may mediate seizure-induced neuronal death. Epileptic seizures are a common feature of mitochondrial dysfunction associated with mitochondrial encephalopathies. Recent work suggests that chronic mitochondrial oxidative stress and resultant dysfunction can render the brain more susceptible to epileptic seizures. This review focuses on the emerging role of oxidative stress and mitochondrial dysfunction both as a consequence and as a cause of epileptic seizures.

Animals↗
PubMed2006

Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells.

AIMS/HYPOTHESIS: Mitochondrial dysfunction is considered a critical component in the development of diabetes. The aim of this study was to elucidate the molecular mechanisms involved in the development of insulin resistance and diabetes through investigation of mitochondrial retrograde signalling. MATERIALS AND METHODS: Mitochondrial function of C2C12 myotube cells was impaired by genetic (ethidium bromide) and metabolic (oligomycin) stress, and changes in target molecules related to insulin signalling were analysed. RESULTS: Concomitant with reductions in mitochondrial membrane potential (DeltaPsim) and ATP synthesis, production of IRS1 and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) were reduced. Moreover, serine phosphorylation of IRS1 increased, resulting in decreased tyrosine phosphorylation. This indicates that mitochondrial dysfunction decreases insulin-stimulated SLC2A4 translocation and glucose uptake. Mitochondrial stress activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) signalling in a Ca(2+)-dependent manner, and removal of free Ca(2+) by BAPTA-AM, as well as inhibition of JNK and p38 MAPK, abrogated mitochondrial stress-induced reductions in IRS1 and SLC2A4 production. Mitochondrial dysfunction after oligomycin treatment significantly increased levels of activating transcription factor 3 (ATF3), which represses Irs1 promoter activity. Removal of the 5' flanking region of Irs1 demonstrated that the promoter region within 191 bases from the transcription site may be involved in the transcriptional repression of Irs1 by mitochondrial stress. CONCLUSIONS/INTERPRETATION: We show distinct mitochondrial retrograde signalling, where Irs1 is downregulated through ATF3 in a Ca(2+)-, JNK- and p38 MAPK-dependent manner, and IRS1 is inactivated. Therefore, mitochondrial dysfunction causes aberrant insulin signalling and abnormal utilisation of glucose, as observed in many insulin resistance states.

Animals↗
PubMed1992

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts.

The cardioprotective effects of a high dose of ascorbate on ischemia-reperfusion-induced myocardial damage were investigated using open chest anesthetized dogs. Two-hour occlusion of the left anterior descending coronary artery (LAD) induced mitochondrial dysfunction with a depletion of mitochondrial glutathione (GSH) concentration. Two-hour LAD occlusion followed by 1-h reperfusion worsened the ischemia-induced mitochondrial dysfunction together with a marked depletion of mitochondrial GSH concentration. Ascorbate reduced the mitochondrial dysfunction and prevented the depletion of mitochondrial GSH concentration after 2-h LAD occlusion and 1-h reperfusion. Activities of mitochondrial glutathione peroxidase and glutathione reductase did not change significantly in each group. Administration of ascorbate also prevented reperfusion arrhythmias without affecting blood pressure or heart rate. These results suggest that coronary reperfusion induces mitochondrial dysfunction and a depletion of mitochondrial GSH concentration, and that a high dose of ascorbate prevents reperfusion damage.

Animals↗
PubMed2006

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes.

Several mitochondrial pathologies are characterized by lipid redistribution and microvesicular cell phenotypes resulting from triglyceride accumulation in lipid-metabolizing tissues. However, the molecular mechanisms underlying abnormal fat distribution induced by mitochondrial dysfunction remain poorly understood. In this study, we show that inhibition of respiratory complex III by antimycin A as well as inhibition of mitochondrial protein synthesis trigger the accumulation of triglyceride vesicles in 3T3-L1 fibroblasts. We also show that treatment with antimycin A triggers CREB activation in these cells. To better delineate how mitochondrial dysfunction induces triglyceride accumulation in preadipocytes, we developed a low-density DNA microarray containing 89 probes, which allows gene expression analysis for major effectors and/or markers of adipogenesis. We thus determined gene expression profiles in 3T3-L1 cells incubated with antimycin A and compared the patterns obtained with differentially expressed genes during the course of in vitro adipogenesis induced by a standard pro-adipogenic cocktail. After an 8-day treatment, a set of 39 genes was found to be differentially expressed in cells treated with antimycin A, among them CCAAT/enhancer-binding protein alpha (C/EBPalpha), C/EBP homologous protein-10 (CHOP-10), mitochondrial glycerol-3-phosphate dehydrogenase (GPDmit), and stearoyl-CoA desaturase 1 (SCD1). We also demonstrate that overexpression of two dominant negative mutants of the cAMP-response element-binding protein CREB (K-CREB and M1-CREB) and siRNA transfection, which disrupt the factor activity and expression, respectively, inhibit antimycin-A-induced triglyceride accumulation. Furthermore, CREB knockdown with siRNA also downregulates the expression of several genes that contain cAMP-response element (CRE) sites in their promoter, among them one that is potentially involved in synthesis of triglycerides such as SCD1. These results highlight a new role for CREB in the control of triglyceride metabolism during the adaptative response of preadipocytes to mitochondrial dysfunction.

3T3-L1 Cells↗
PubMed2004

Skeletal muscle aging in F344BN F1-hybrid rats: I. Mitochondrial dysfunction contributes to the age-associated reduction in VO2max.

Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the decline in muscle mass-specific skeletal muscle aerobic function is unknown. We used a pump-perfused rat hind-limb model to examine maximal aerobic performance (VO(2max)) in young adult (YA; 8-9-month-old), late middle aged (LMA; 28-30-month-old) and senescent (SEN; 36-month-old) Fischer 344 x Brown Norway F1-hybrid rats at matched rates of convective O(2) delivery (QO(2)). Despite similar muscle QO(2) during a 4-minute contraction bout, muscle mass-specific VO(2max) was reduced in LMA (15%) and SEN (52%) versus YA. In plantaris muscle homogenates, nested polymerase chain reaction revealed an increased frequency of mitochondrial DNA deletions in the older animals. A greater reduction in the flux through electron transport chain complexes I-III than citrate synthase activity in the older animals suggests mitochondrial dysfunction consequent to mitochondrial DNA damage with aging. These results support the hypothesis that a reduced oxidative capacity, due in part to age-related mitochondrial dysfunction, contributes to the decline in aerobic performance in aging skeletal muscles.

Aerobiosis↗
PubMed1994

Oxidative stress and mitochondrial dysfunction in neurodegeneration.

In the last 4 years much progress has been made in the understanding of mitochondrial disorders. Point-mutations, deletions and depletion of the mitochondrial genome are associated with disorders like Leber's disease, MERRF (Myoclonus Epilepsia with Ragged Red Fibers), MELAS (mitochondrial Myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes) and several others. Recently, mitochondrial dysfunctions have been also related to neurodegenerative disorders like Parkinson's disease and to aging. Since the brain depends mostly on mitochondrial energy supply, mitochondrial dysfunctions may affect the nervous system more severely than other tissues causing or worsening diseases and playing a role in the biological deterioration of aging. Furthermore, the mitochondrial energy supply is associated with the production of highly reactive oxygen species. Ninety-five percent of the molecular oxygen is metabolized within the mitochondria by the electron-transport chain so that mitochondria are highly exposed to oxidative stress which may damage selected neuronal populations. Oxygen radicals created during respiration induce mitochondrial dysfunction which accelerates the production of more deleterious species of oxygen. The latter step further increases mitochondrial malfunction, thus intensifying and perpetuating the cycle. These two mechanisms combined may lead to cell death in brain and other tissues with high metabolic rate. Therefore, in neurodegenerative disorders such as Parkinson's disease mitochondrial dysfunction and oxidative stress may cause or worsen the clinical features.

Antioxidants↗
PubMed2003

The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death.

Genotoxic stresses stabilize the p53 tumor suppressor protein which, in turn, transactivates target genes to cause apoptosis. Although Noxa, a "BH3-only" member of the Bcl-2 family, was shown to be a target of p53-mediated transactivation and to function as a mediator of p53-dependent apoptosis through mitochondrial dysfunction, the molecular mechanism by which Noxa causes mitochondrial dysfunction is largely unknown. Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria. Noxa-induced cytochrome c release is inhibited by permeability transition pore inhibitors such as CsA or MgCl2, and Noxa induces an ultra-structural change of mitochondria yielding "swollen" mitochondria that are unlike changes induced by tBid. This indicates that Noxa may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol. Moreover, Bak-oligomerization, which is an essential event for tBid-induced cytochrome c release in the extrinsic death signaling pathway, is not associated with Noxa-induced cytochrome c release. This finding suggests that the pathway of Noxa-induced mitochondrial dysfunction is distinct from the one of tBid-induced mitochondrial dysfunction. Thus, we propose that there are at least two different pathways of mitochondrial dysfunction; one mediated through Noxa in response to genotoxic stresses and the other through tBid in response to death ligands.

Amino Acid Sequence↗
PubMed2005

Mitochondrial dysfunction and its role in motor neuron degeneration in ALS.

Mitochondria play a pivotal role in many metabolic and apoptotic pathways that regulate the life and death of cells. Accumulating evidence suggests that mitochondrial dysfunction is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mitochondrial dysfunction may cause motor neuron death by predisposing them to calcium-mediated excitotoxicity, by increasing generation of reactive oxygen species, and by initiating the intrinsic apoptotic pathway. Morphological and biochemical mitochondrial abnormalities have been described in sporadic human ALS cases, but the implications of these findings in terminally ill individuals or in post-mortem tissues are difficult to decipher. However, remarkable mitochondrial abnormalities have also been identified in transgenic mouse models of familial ALS expressing mutant Cu, Zn superoxide dismutase (SOD1). Detailed studies in these mouse models indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting that mitochondrial dysfunction may be causally involved in the pathogenesis of ALS. Although the mechanisms whereby mutant SOD1 damages mitochondria remain to be fully understood, the finding that a portion of mutant SOD1 is localized in mitochondria, where it forms aberrant aggregates and protein interactions, has opened a number of avenues of investigation. The future challenges are to devise models to better understand the effects of mutant SOD1 in mitochondria and the relative contribution of mitochondrial dysfunction to the pathogenesis of ALS, as well as to identify therapeutic approaches that target mitochondrial dysfunction and its consequences.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine.

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.

Actins↗
PubMed2006

Mitochondrial dysfunction and amyotrophic lateral sclerosis.

The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are still unknown. Several lines of evidence suggest that mitochondrial dysfunction may be involved in the pathogenesis of ALS. Biochemical and morphological mitochondrial abnormalities have been demonstrated in postmortem spinal cords of ALS patients. Furthermore, in transgenic mice expressing mutant Cu,Zn-superoxide dismutase (SOD1), the antioxidant enzyme associated with familial ALS (FALS), mitochondrial abnormalities precede the disease onset, suggesting that mitochondrial dysfunction is causally involved in the pathogenesis of SOD1-FALS. Despite this evidence, it is not yet fully understood how mutant SOD1 damages mitochondria. Recent work has demonstrated that a portion of mutant SOD1 is localized in mitochondria, both in transgenic mice and in FALS patients, where it forms proteinaceous aggregates. These findings have opened new avenues of investigation addressing the hypothesis that mutant SOD1 may directly damage mitochondria. Major future challenges will be to better understand the mechanisms and the consequences of mitochondrial dysfunction in ALS. If mitochondrial dysfunction is convincingly involved in ALS pathogenesis, either as a primary cause or as contributing factor, it is likely to become a novel target for therapeutic intervention.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells.

Initiation of apoptosis by many agents is preceded by mitochondrial dysfunction and depolarization of the mitochondrial inner membrane. Here we demonstrate that, in renal proximal tubular cells (RPTC), cisplatin induces mitochondrial dysfunction associated with hyperpolarization of the mitochondrial membrane and that these events are mediated by protein kinase C (PKC)-alpha and ERK1/2. Cisplatin induced sustained decreases in RPTC respiration, oxidative phosphorylation, and increases in the mitochondrial transmembrane potential (deltaPsi(m)), which were preceded by the inhibition of F(0)F(1)-ATPase and cytochrome c release from the mitochondria, accompanied by caspase-3 activation, and followed by RPTC apoptosis. Cisplatin also decreased active Na+ transport as a result, in part, of the inhibition of Na+/K(+)-ATPase. These changes were preceded by PKC-alpha and ERK1/2 activation. Inhibition of cisplatin-induced PKC-alpha and ERK1/2 activation using Go6976 and PD98059, respectively, abolished increases in deltaPsi(m), diminished decreases in oxidative phosphorylation, active Na+ transport, and decreased caspase-3 activation without blocking cytochrome c release. Caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) did not prevent increases in deltaPsi(m). Furthermore, inhibition of PKC-alpha did not prevent cisplatin-induced ERK1/2 activation. We concluded that in RPTC: 1) cisplatin-induced mitochondrial dysfunction, decreases in active Na+ transport, and apoptosis are mediated by PKC-alpha and ERK1/2; 2) PKC-alpha and ERK1/2 mediate activation of caspase-3 by acting downstream of cytochrome c release from mitochondria; and 3) ERK1/2 activation by cisplatin occurs through a PKC-alpha-independent pathway.

Adenosine Triphosphate↗