Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “mitochondrial dysfunction”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources
PubMed1983

The effects of verapamil on mitochondrial dysfunction associated with coronary reperfusion.

In order to clarify the protective mechanism of verapamil, the following experiment was performed. Twenty-four anesthetized dogs were divided into 3 groups of 8 animals each. In the first, the left anterior descending coronary artery (LAD) was occluded for 15 min; in the second, 5-min reperfusion was done following a 15-min occlusion; in the third, prior to 5-min reperfusion, verapamil (0.4 mg/kg) was infused for 5 min. In each group, heart mitochondria were prepared from the normal and occluded or reperfused areas and their functions were estimated polarographically. The contents of calcium, phospholipids and fatty acids in the mitochondria were also measured by atomic absorption spectrophotometry, Allen's method and gas chromatography, respectively. Although occlusion induced mitochondrial dysfunction, the dysfunction was exacerbated by reperfusion. Occlusion alone did not alter the contents of calcium, phospholipids and fatty acids in mitochondria, while occlusion and subsequent reperfusion increased calcium and fatty acids and decreased phospholipids in mitochondria. Verapamil prevented these reperfusion responses. These results suggest that reperfusion injury of mitochondria is based on the degradation of mitochondrial phospholipids, which is caused by an activation of phospholipase, being triggered by a calcium increase. Verapamil, a calcium antagonist, might protect against reperfusion injury by inhibiting the activation of phospholipase.

Animals↗
PubMed1989

Effect of 3-(2,2,2-trimethylhydrazinium) propionate, gamma-butyrobetaine hydroxylase inhibitor, on isoproterenol-induced mitochondrial dysfunction.

The present study was designed to investigate whether or not reduction of carnitine content could protect isoproterenol (ISP)-induced myocardial injury using 3-(2,2,2-trimethylhydrazinium) propionate (TMHP), gamma-butyrobetaine hydroxylase inhibitor. Rats were divided into 4 groups; the control group: untreated, the TMHP-1 group: TMHP (100 mg/kg) was administered intraperitoneally, and ISP (10 mg/kg) was administered subcutaneously on the following day, the TMHP-7 group: TMHP (100 mg/kg) for 7 successive days, and ISP (10 mg/kg) on the eighth day, the ISP group: ISP (10 mg/kg) was administered. Rats were cervically dislocated 15 hours after ISP administration, and heart mitochondrial electron-transport activity (NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) were measured enzymatically. Activity of succinate-cytochrome c reductase was not affected significantly by ISP, however, NADH-cytochrome c reductase and cytochrome c oxidase were significantly reduced in the ISP and TMHP groups. Administration with TMHP for 7 successive days lessened the reduction of the activities. Mitochondrial electron-transport system plays an important role in cellular energy transduction. These results suggested that mitochondrial dysfunction induced by ISP is related to carnitine-dependent fatty acid metabolism and that TMHP reduces the myocardial injury.

Animals↗
PubMed1999

Apoptotic changes precede mitochondrial dysfunction in red cell-type pyruvate kinase mutant mouse erythroleukemia cell lines.

Two erythroleukemia cell lines have been established from the splenic lesions of red blood cell-type pyruvate kinase (R-PK) activity-deficient mice of CBA/N origin infected with a polycythemic strain of Friend leukemia virus complex (FVp). Ten to 30% of the cells of these cell lines undergo apoptotic changes in routine passage, as shown by nuclear fragmentation, DNA laddering, DNA content (propidium iodide (PI) staining), and annexin V binding assay. In these cells, however, although adenosine 5'-triphosphate (ATP) levels were lower than in the control cells, the mitochondrial inner transmembrane potential (delta psi m), detected by rhodamine 123 (R123) and diSC3(5) staining, remained unchanged until the final stage of apoptosis. No evidence was obtained to relate this finding to R-PK mutation due to difficulty in cloning stable, conditionally inducible R-PK gene transfectants. However, low delta psi m in the apoptotic cell population of the control T3-K-1 (K-1) and T3-CI-2-0 (2-0) Friend erythroleukemia cells supports a possible relationship, as do results obtained in two Friend erythroleukemia cells recently isolated from normal CBA/N mice. These cell lines are expected to be useful for clarifying both the primary apoptotic changes independent of mitochondrial dysfunction and the PK-isozyme changes during erythrodifferentiation, for example, the decreased muscle type 2 (M2) PK level. Modification of growth signals in these cell lines may modulate differentiation and/or apoptosis and allow further elucidation of the signaling networks.

Adenosine Triphosphate↗
PubMed1999

Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis.

Hereditary tyrosinemia type I is the most severe metabolic disease of the tyrosine catabolic pathway mainly affecting the liver. It is caused by deficiency of fumarylacetoacetate hydrolase, which prevents degradation of the toxic metabolite fumarylacetoacetate (FAA). We report here that FAA induces common effects (i.e., cell cycle arrest and apoptosis) in both human (HepG2) and rodent (Chinese hamster V79) cells, effects that seem to be temporally related. Both the antiproliferative and apoptosis-inducing activities of FAA are dose dependent and enhanced by glutathione (GSH) depletion with L-buthionine-(S,R)-sulfoximine (BSO). Short treatment (2 h) with 35 microM FAA/+BSO or 100 microM FAA/-BSO induced a transient cell cycle arrest at the G2/M transition (20% and 37%, respectively) 24 h post-treatment. In cells treated with 100 microM FAA/-BSO, an inactivation, followed by a rapid over-induction of cyclin B-dependent kinase occurred, which peaked 24 h post-treatment. Maximum levels of caspase-1 and caspase-3 activation were detected at 3 h and 32 h, respectively, whereas release of mitochondrial cytochrome c was maximal at 24-32 h post-treatment. The G2/M peak declined 24 h later, concomitantly with the appearance of a sub-G1, apoptotic population showing typical nucleosomal-sized DNA fragmentation and reduced mitochondrial transmembrane potential (Deltapsi(m)). These events were prevented by the general caspase inhibitor z-VAD-fmk, whereas G2/M arrest and subsequent apoptosis were abolished by GSH-monoethylester or N-acetylcysteine. Other tyrosine metabolites, maleylacetoacetate and succinylacetone, had no antiproliferative effects and induced only very low levels of apoptosis. These results suggest a modulator role of GSH in FAA-induced cell cycle disturbance and apoptosis where activation of cyclin B-dependent kinase and caspase-1 are early events preceding mitochondrial cytochrome c release, caspase-3 activation, and Deltapsi(m) loss. -Jorquera, R., Tanguay, R. M. Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis.

Acetoacetates↗
PubMed1999

Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration.

Synapses are often located at great distances from the cell body and so must be capable of transducing signals into both local and distant responses. Although progress has been made in understanding biochemical cascades involved in neuronal death during development of the nervous system and in various neurodegenerative disorders, it is not known whether such cascades function locally in synaptic compartments. Prostate apoptosis response-4 (Par-4) is a leucine zipper and death domain-containing protein that plays a role in neuronal apoptosis. We now report that Par-4 levels are rapidly increased in cortical synaptosomes and in dendrites of hippocampal neurons in culture and in vivo, following exposure to apoptotic or excitotoxic insults. Par-4 expression is regulated at the translational level within synaptic compartments. Par-4 antisense treatment suppressed mitochondrial dysfunction and caspase activation in synaptosomes and prevented death of cultured hippocampal neurons following exposure to excitotoxic and apoptotic insults. Local translational regulation of death-related proteins in synaptic compartments may play a role in programmed cell death, adaptive remodeling of synapses, and neurodegenerative disorders.

Animals↗
PubMed2001

Amphotericin B potentiates the activation of inducible nitric oxide synthase and causes nitric oxide-dependent mitochondrial dysfunction in cytokine-treated rodent astrocytes.

Because the neurotoxic effects of the antifungal drug amphotericin B (AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes. AMB caused a dose-dependent increase of NO generation in interferon-gamma (IFN-gamma)-stimulated rat and mouse astrocytes, as well as in IFN-gamma + tumor necrosis factor-alpha (TNF-alpha)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor IRF-1. The activation of transcription factor NF-kappaB was apparently required for AMB-induced iNOS mRNA expression, as the latter was abolished by NF-kappaB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-gamma + AMB treatment led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity toward IFN-gamma-stimulated astrocytes was dependent on both AMB and NO action, since AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial dysfunction. These results suggest that the enhancement of cytokine-induced iNOS activation in astrocytes and the subsequent release of high amounts of NO might be at least partly responsible for AMB neurotoxicity.

Amphotericin B↗
PubMed1998

Mitochondrial dysfunction of human muscle in chronic alcoholism detected by using 31P-magnetic resonance spectroscopy and near-infrared light absorption.

We previously examined the effect of alcohol on muscle energy metabolism in chronic alcoholics by using 31P-magnetic resonance spectroscopy. Measurements of intracellular pH and PCr index [PCr/(PCr + Pi)] during resting, hand grasping, and recovery in the left flexor digitorum superficialis muscle of alcoholics with neurological signs showed a marked decrease and delayed recovery of pH, but rapid recovery of PCr index indicating that the muscle produces lactate during and after exercise to maintain the ATP level. To clarify the reason for this preference for anaerobic metabolism, we conducted simultaneous measurements of the muscle blood supply during and after exercise by using the near-infrared light method and energy metabolism by using 31P-magnetic resonance spectroscopy. In alcoholics with neurological signs, we observed a significant increase of oxyhemoglobin after exercise with a slight increase of total hemoglobin. In healthy volunteers and chronic alcoholics without neurological signs, such an overshoot of oxyhemoglobin was not observed. We conclude that chronic alcoholics with neurological signs have an abnormality of aerobic metabolism owing to muscle mitochondrial dysfunction.

Acid-Base Equilibrium↗
PubMed1989

Metabolic changes and mitochondrial dysfunction early following transthoracic countershock in dogs.

The mechanisms of myocardial injury and necrosis following transthoracic shocks from a direct current cardiac defibrillator were investigated in adult greyhounds. Myocardial lactate extraction became negative maximally at 1 minute, following two (mean -22% +/- SEM23) or five (-193% +/- 135) shocks and returned to baseline in 6-15 minutes. Myocardial necrosis assessed at 4 hours following the shock period was 0.05 g (+/- 0.03) after two shocks, 6.69 g (+/- 1.76) after five shocks and zero in controls. In further experiments, dogs received five or zero (dummy) shocks and mitochondria were isolated from their hearts following excision within 1 minute of receiving the final shock. Maximal oxygen consumption in right ventricular mitochondria was lower than the unshocked controls with both glutamate (66.9 +/- 9.4 nanoatoms of oxygen/mg per minute, n = 9 vs 86.6 +/- 13.6 nanoatoms/mg per minute, n = 7) and succinate (96.2 +/- 8.7 nanoatoms/mg per minute, n = 9 vs 119.5 +/- 14.4 nanoatoms/mg per minute, n = 7) as substrates. Using electron spin resonance spectroscopy, an increase in a peroxyl-free radical with g = 2.031 was detected in myocardial tissue after two internal shocks (50 joules stored energy, 0.5-minute intervals). We conclude that mitochondrial dysfunction and free-radical generation are likely contributors to cellular injury following multiple countershocks.

Animals↗
PubMed2001

Lung mitochondrial dysfunction in pulmonary hypertension syndrome. I. Site-specific defects in the electron transport chain.

The main objectives of this study were to determine a) site-specific defects in the electron transport chain of lung mitochondria of broilers with pulmonary hypertension syndrome (PHS), b) if these defects are attenuated by high dietary vitamin E, and c) if these defects have a genetic basis. In Experiment 1, lung mitochondria were isolated from broilers with and without PHS fed diets containing 15 IU and 100 IU dl-alpha-tocopherol acetate/kg (VE); the four treatments were control, VE, PHS, and VE-PHS, respectively. Hydrogen peroxide (H2O2) generation in isolated lung mitochondria was monitored by dichlorofluorosein (DCF) fluorescence in response to chemicals that inhibit electron flow at specific sites on the electron transport chain using a 96-well microplate with Cytoflour (excitation/emission 480/530 nm). Basal H2O2 production was higher in PHS than in control mitochondria. Differences in H2O2 production between control and PHS were magnified by inhibition of Complexes I and III (Coenzyme Q) of the respiratory chain in mitochondria. Functional defects in PHS mitochondria were attenuated by high dietary VE. In Experiment 2, basal H2O2 production and that following inhibition of Complexes I and III were lower in lung mitochondria isolated from broilers selected for genetic resistance to PHS than in nonselected birds in the base population. The results of this study indicate that site-specific defects in Complexes I and III may underlie lung mitochondrial dysfunction in broilers with PHS, that these defects are attenuated by high dietary vitamin E, and that these defects may be related to genetic predisposition to PHS.

Animals↗
PubMed2001

Glycated high-density lipoprotein induces apoptosis of endothelial cells via a mitochondrial dysfunction.

Glycation of plasma proteins may contribute to an excess risk of developing atherosclerosis in patients with diabetes mellitus. Although it is believed that high-density lipoprotein (HDL) is nonenzymatically glycosylated at an increased level in diabetic individuals, little is known about a possible linkage between glycated HDL and endothelium dysfunction in diabetes. This study set out to clarify whether glucose-modified HDL affects the function of endothelial cells by examining the apoptosis of cultured human aortic endothelial cells (HAECs) exposed to a glycated-oxidized HDL (gly-ox-HDL) prepared in vitro. Incubation of HAECs with 100 microg/ml of gly-ox-HDL for 48 h showed apoptotic features, such as cell shrinkage, membrane blebbing, and concentration and fragmentation of the nucleus, and the degree of apoptosis was dose-dependent on the glucose used in the preparation of gly-ox-HDL. Stimulation of HAECs with gly-ox-HDL elicited a marked increase in caspase 3 activity and the expressions of active caspase 3 and caspase 9, whereas concomitant treatment with a caspase 3 inhibitor significantly blocked gly-ox-HDL-induced apoptosis of HAECs. The release of cytochrome c into cytosols markedly increased in HAECs during the treatment with gly-ox-HDL. The increased expressions of Bax and Bad were detected in HAECs incubated for 24 h with gly-ox-HDL, but gly-ox-HDL failed to interfere with the expression of Bcl-2 and Bcl-x. Moreover, in vitro experiments with HDL (gly-HDL) glycated in the presence of 2 mM EDTA and Cu(2+)-oxidized HDL suggested that the apoptotic effect of gly-ox-HDL on endothelial cells might be due to an additional oxidative modification of gly-HDL. Taken altogether, additional oxidation of HDL under hyperglycemic conditions may induce endothelial apoptosis through a mitochondrial dysfunction, following the deterioration of vascular function.

Aorta↗
PubMed1996

Mitochondrial dysfunction after fetal alcohol exposure.

Specific mitochondrial enzyme activities and mRNA levels were measured in the heart, brain, and liver tissues of a group of 1-day-old neonatal rats whose mothers were alcohol-fed during pregnancy and compared with a control group. The results show a significant decrease in mitochondrial ATP synthase activity in both the brain and liver, as well as a decrease in complex III activity in the liver of rats exposed to alcohol. Other mitochondrial enzymes activities (e.g., citrate synthase, cytochrome c oxidase, and complex I), as well as specific mitochondrial transcript levels, were not significantly affected. Heart mitochondrial enzyme activities were not significantly affected. These data reveal that a tissue-specific response occurs after fetal exposure to alcohol and may explain some of the cellular events occurring in fetal alcohol syndrome resulting in abnormal growth and neurological development.

ATP Synthetase Complexes↗
PubMed2001

Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin.

Interference with mitochondrial calcium regulation is proposed to be a primary causative event in the mechanism of doxorubicin-induced cardiotoxicity. We previously reported disruption of mitochondrial calcium homeostasis after chronic doxorubicin administration (Solen et al. Toxicol. Appl. Pharmacol, 129: 214-222, 1994). The present study was designed to characterize the dose-dependent and cumulative interference with mitochondrial calcium regulation and to assess the reversibility of this functional lesion. Sprague Dawley rats were treated with 2 mg/kg/week doxorubicin s.c. for 4-8 weeks. With succinate as substrate, cardiac mitochondria isolated from rats after 4 weeks of treatment with doxorubicin expressed a lower calcium loading capacity compared with control. This suppression of calcium loading capacity increased with successive doses to 8 weeks of treatment (P < 0.05) and persisted for 5 weeks after the last doxorubicin injection, and was corroborated by dose-dependent and irreversible histopathological changes. Preincubation of mitochondria with tamoxifen, DTT, or monobromobimane did not reverse the diminished calcium loading capacity caused by doxorubicin. In contrast, incubation with cyclosporin A abolished any discernible difference in mitochondrial calcium loading capacity between doxorubicin-treated and saline-treated rats. The decrease in cardiac mitochondrial calcium loading capacity was not attributable to bioenergetic changes in the electron transport chain, because the mitochondrial coupling efficiency was not altered by doxorubicin treatment. However, the ADP/ATP translocase content was significantly lower in mitochondria from rats that received 8 weeks of doxorubicin treatment. These data indicate that doxorubicin treatment in vivo causes a dose-dependent and irreversible decrease in mitochondrial calcium loading capacity. Suppression of adenine nucleotide translocase content may be a key factor altering the calcium-dependent regulation of the mitochondrial permeability transition pore, which may account for the cumulative and irreversible loss of myocardial function in patients receiving doxorubicin chemotherapy.

Animals↗
PubMed1996

Mitochondrial dysfunction in spontaneous inbred turkey cardiomyopathy.

Mitochondrial enzyme activities were examined in cardiac tissues of turkeys with spontaneous inbred cardiomyopathy. Marked declines in specific enzyme activities were noted for respiratory complexes III and V ranging from 65-90% of the control values. No significant differences in complexes I, IV and citrate synthase nor in mitochondrial DNA copy number were detected. These results suggest that specific mitochondrial enzyme defects occur in cardiac tissues during spontaneous inbred turkey cardiomyopathy.

Animals↗
PubMed1996

[Migraine and mitochondrial dysfunction].

Like many others neurological diseases, mitochondrial involvement, by means of abnormalities in cerebral oxidative metabolism, may play a role in migraine. This review summarizes clinical data, in vivo magnetic resonance spectroscopy studies, biochemical assays and therapeutic results that support the "mitochondrial hypothesis of migraine".

Brain↗
PubMed1994

Lipid hydroperoxide induced mitochondrial dysfunction following acute ethanol intoxication in rats. The critical role for mitochondrial reduced glutathione.

It has been found that acute ethanol (EtOH) intoxication of rats caused depletion of mitochondrial reduced glutathione (GSH) of approximately 40%. A GSH reduction of similar extent was also observed after the administration to rats of buthionine sulphoximine (BSO), a specific inhibitor of GSH synthesis. Combined treatment with BSO plus EtOH further decreased mitochondrial GSH up to 70% in comparison to control. Normal functional efficiency was encountered in BSO-treated mitochondria, as evaluated by membrane potential measurements during a complete cycle of phosphorylation. In contrast a partial loss of coupled functions occurred in mitochondria from EtOH- and BSO plus EtOH-treated rats. The presence in the incubation system of either GSH methyl monoester (GSH-EE), which normalizes GSH levels, or of EGTA, which chelates the available Ca2+, partially restores the mitochondrial phosphorylative efficiency. Following EtOH and BSO plus EtOH intoxication, the presence of fatty-acid-conjugated diene hydroperoxides, such as octadecadienoic acid hydroperoxide (HPODE), was detected in the mitochondrial membrane. Exogenous HPODE, when added to BSO-treated mitochondria, induced, in a concentration-dependent system, membrane potential derangement. The presence of either GSH-EE or EGTA fully prevented a drop in membrane potential. The results obtained suggest that fatty acid hydroperoxides, endogenously formed during EtOH metabolism, brought about non-specific permeability changes in the mitochondrial inner membrane whose extent was strictly dependent on the level of mitochondrial GSH.

Alcoholic Intoxication↗
PubMed1995

Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes.

Mitochondrial glutathione plays an important role in maintaining a functionally competent organelle. Previous studies have shown that ethanol feeding selectively depletes the mitochondrial glutathione pool, more predominantly in mitochondria from perivenous hepatocytes. Because S-adenosyl-L-methionine (SAM) is a glutathione precursor and maintains the structure and function of biological membranes, the purpose of the present study was to determine the effects of SAM on glutathione and function of perivenous (PV) and periportal (PP) mitochondria from chronic ethanol-fed rats. SAM administration resulted in a significant increase in the basal cytosol and mitochondrial glutathione in both PP and PV cells from both pair-fed or ethanol-fed groups. When hepatocytes from ethanol-fed rats supplemented with SAM were incubated with methionine plus serine or N-acetylcysteine, mitochondrial glutathione increased in parallel with cytosol, an effect not observed in cells from ethanol-fed rats without SAM. Feeding equimolar N-acetylcysteine raised cytosol glutathione but did not prevent the mitochondrial glutathione defect. In addition, SAM feeding resulted in significant preservation of cellular adenosine triphosphate (ATP) levels (23% to 43%), mitochondrial membrane potential (17% to 25%), and the uncoupler control ratio (UCR) of respiration (from 5.1 +/- 0.7 to 7.3 +/- 0.6 and 2.1 +/- 0.3 to 6.1 +/- 0.7) for PP and PV mitochondria, respectively. Thus, these effects of SAM suggest that it may be a useful agent to preserve the disturbed mitochondrial integrity in liver disease caused by alcoholism through maintenance of mitochondrial glutathione transport.

Administration, Oral↗
PubMed1993

Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders.

Mitochondrial myopathies and defects in oxidative phosphorylation have been described in some patients with peroxisomal disorders. Although peroxisomes and mitochondria play a role in the beta-oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal beta-oxidation are associated with extracellular accumulation of very long-chain fatty acids and may be accompanied by alterations in the intracellular pool of fatty acyl-CoAs, which are known to alter mitochondrial function. This study was initiated to examine alterations in the intracellular pool of acyl-CoAs and mitochondrial function in two children with generalized disorders of peroxisomal function and clinical lactic/pyruvic acidaemia. Fibroblasts were cultured from skin biopsies obtained from one child with neonatal adrenoleukodystrophy (NALD) and another with rhizomelic chondrodysplasia punctata (RCDP). Fibroblast lactate oxidation was significantly inhibited in NALD by 76% and RCDP by 92% compared to control values of 1.9 +/- 0.1 nmol/min per mg protein. Pyruvate dehydrogenase (PDH) (mean +/- SEM; activity nmol/min per mg protein) was: NALD 0.55 +/- 0.02 (p < 0.01), RCDP 0.44 +/- 0.02 (P < 0.01), and controls 0.83 +/- 0.02. The acid-insoluble (long-chain and very long-chain) acyl-CoA levels (mean +/- SEM; pmol/mg protein) were: NALD 129 +/- 69 (p < 0.01), RCDP 65 +/- 15 (p < 0.05), and control 45 +/- 7. These two patients with generalized peroxisomal disorders exhibited an increase in intracellular acyl-CoA species accompanied by decreased PDH activity and clinical lactic/pyruvic acidaemia.

Acidosis, Lactic↗
PubMed2000

Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates.

Kidney proximal tubule cells developed severe energy deficits during hypoxia/reoxygenation not attributable to cellular disruption, lack of purine precursors, the mitochondrial permeability transition, or loss of cytochrome c. Reoxygenated cells showed decreased respiration with complex I substrates, but minimal or no impairment with electron donors at complexes II and IV. This was accompanied by diminished mitochondrial membrane potential (DeltaPsi(m)). The energy deficit, respiratory inhibition, and loss of DeltaPsi(m) were strongly ameliorated by provision of alpha-ketoglutarate plus aspartate (alphaKG/ASP) supplements during either hypoxia or only during reoxygenation. Measurements of (13)C-labeled metabolites in [3-(13)C]aspartate-treated cells indicated the operation of anaerobic pathways of alphaKG/ASP metabolism to generate ATP, yielding succinate as end product. Anaerobic metabolism of alphaKG/ASP also mitigated the loss of DeltaPsi(m) that occurred during hypoxia before reoxygenation. Rotenone, but not antimycin or oligomycin, prevented this effect, indicating that electron transport in complex I, rather than F(1)F(0)-ATPase activity, had been responsible for maintenance of DeltaPsi(m) by the substrates. Thus, tubule cells subjected to hypoxia/reoxygenation can have persistent energy deficits associated with complex I dysfunction for substantial periods of time before onset of the mitochondrial permeability transition and/or loss of cytochrome c. The lesion can be prevented or reversed by citric acid cycle metabolites that anaerobically generate ATP by intramitochondrial substrate-level phosphorylation and maintain DeltaPsi(m) via electron transport in complex I. Utilization of these anaerobic pathways of mitochondrial energy metabolism known to be present in other mammalian tissues may provide strategies to limit mitochondrial dysfunction and allow cellular repair before the onset of irreversible injury by ischemia or hypoxia.

Adenosine Triphosphate↗