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 109 records · Page 6Linked to original sources
PubMed1995

Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood.

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using 31P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three-fold greater than in control subjects. However, the initial rate of ATP turnover at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.

Adolescent↗
PubMed1989

Carnitine deficiency, mitochondrial dysfunction and the heart. Identical defect of oxidative phosphorylation in muscle mitochondria in cardiomyopathy due to carnitine loss and in Duchenne muscular dystrophy.

Cardiomyopathies are often caused by a metabolic defect. Carnitine deficiency and mitochondrial defects in the metabolism of acyl-CoA, including defects in oxidative phosphorylation, start the same circular mechanism of mitochondrial doom. Patients with cardiomyopathy due to carnitine loss are cured by carnitine supplementation. In such a patient we found defective oxidative phosphorylation in isolated muscle mitochondria. The stimulation of the respiratory rate with all substrates by ADP was decreased, probably the cause of inhibition of the adenine nucleotide translocator by accumulating long-chain acyl-CoA. The same condition was encountered in patients with Duchenne muscular dystrophy, who often get cardiomyopathy in the course of the disease process.

Acetyl Coenzyme A↗
PubMed1993

Free radicals and mitochondrial dysfunction in Parkinson's disease.

The precise relationship of the complex I deficiency in PD to the dopaminergic cell death and aetiology of this disorder is as yet unknown. However, evidence is accruing that this mitochondrial defect may play a central role in the cascade of events that terminates in nigral neuronal loss. Further work needs to be carried out to determine the molecular mechanisms that underlie the complex I deficiency as these may provide important indicators to the ultimate cause of PD. This may involve a genetic abnormality of complex I that may convey a susceptibility to developing PD. Alternatively, exogenous or endogenous toxic agents may target nigral complex I along pathways similar to those recognized for MPTP. A combination of a genetic predisposition in addition to an environmental precipitant has gained substantial support as an explanation for the cause of PD.

Cell Death↗
PubMed1988

Effect of a novel thromboxane A2 synthetase inhibitor on ischemia-induced mitochondrial dysfunction in canine hearts.

This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Mitochondrial dysfunction induced by pancreatitis-associated ascitic fluid.

Acute hemorrhagic pancreatitis (AHP) involves multiple organ failure probably caused by the toxic factor(s) released in pancreatitis-associated ascitic fluid (PAAF). We found that PAAF interferes with hepatic mitochondrial respiration resulting in severe disturbances in respiratory control (RCR) and ADP/O ratios. Pancreatitis was induced in dogs by retrograde pancreatic duct infusion and the resultant PAAF was centrifuged, filtered, and frozen until used. Two human PAAFs collected from AHP patients were treated in a similar manner. Rat liver mitochondrial oxygen uptake was measured at 30 degrees C before and after addition of ADP and PAAF. Paired control runs were made using pooled heat-inactivated dog serum. Tests with nine canine PAAFs showed a mean increase of 120% in state 4 respiration (P less than 0.0001). After exposure to PAAF, addition of ADP to previously coupled mitochondria did not induce state 3 respiration. The human PAAFs both showed significant increases in state 4 respiration (P less than 0.01) and a marked decrease in RCR. Dose-response tests with human and canine PAAFs showed a positive correlation between percentage increase in state 4 respiration and the concentration of PAAF used. These results confirm the presence in PAAF of mitotoxic substance(s) which cause irreversible mitochondrial damage. Inhibition of coupled mitochondrial respiration by PAAF with the resultant fall in ATP may be the causative agent for the tissue and organ damage observed in AHP.

Animals↗
PubMed1992

Mitochondrial dysfunction in the non-obstructed lobe of rat liver after selective biliary obstruction.

In order to elucidate the function of non-obstructed hepatic lobe during partial cholestasis, we have examined the effects of selective biliary obstruction on the mitochondrial energy transducing system in rat liver. The non-ligated lobe became hypertrophic after ligation of the bile ducts that drained 90% of the liver, and there was no increase in the level of serum bilirubin, alkaline phosphatase activity, or bile acids. However, mitochondrial oxidative phosphorylation function, specific enzymic activities of the oxidative phosphorylation complexes, and the subunit contents of these complexes were markedly decreased in the non-obstructed lobe at 4 weeks after the 90% biliary obstruction. There was no increase in the specific content of mitochondrial DNA. The mitochondrial energy transducing system in the non-obstructed lobes is not enhanced, but is significantly impaired during prolonged selective biliary obstruction, despite normal serum biochemical data and hypertrophy of the non-ligated lobe. These results imply early release of obstruction of cholestatic lobe, e.g. by biliary drainage, would be beneficial for maintaining the mitochondrial function in the non-cholestatic lobe.

Animals↗
PubMed1996

Friedreich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction.

Friedreich's ataxia is the most common inherited spinocerebellar ataxia. A decade of linkage and physical mapping studies have culminated in the identification of the Friedreich's ataxia gene. The presence of homologues in purple bacterial genomes, but not in other bacteria, allows us to infer a mitochondrial location for frataxin (Friedreich's ataxia protein) on the basis of bacterial phylogeny. Frataxin possesses a non-globular N-terminus domain providing a candidate mitochondrial targeting peptide. Clues to the function of frataxin are provided by the mitochondrial location, a clinically similar ataxia with vitamin E deficiency, and certain neuropathies with mitochondrial DNA instability caused by mutations in nuclear genes.

Amino Acid Sequence↗
PubMed1993

Mitochondrial dysfunction in alcoholic patients as assessed by breath analysis.

Mitochondria of patients with alcoholic liver disease are morphologically abnormal, and mitochondria isolated from animals exposed to ethanol exhibit functional deficiencies in vitro. Because the functional consequences of the morphological alterations and the relevance of in vitro observations to mitochondrial function in alcoholic subjects are not clear, we assessed mitochondrial function noninvasively with a breath test. Mitochondrial function was assessed by measuring the exhalation of 14CO2 after administration of 1 microCi 2-keto[1-14C]isocaproic acid, the decarboxylation of which occurs in mitochondria. The results of the 2-keto[1-14C]isocaproic acid breath test in 17 alcoholic subjects were compared with the results in healthy controls and patients with nonalcoholic liver disease. The peak exhalation of 14CO2 and the fraction of the administered dose decarboxylated in 60 min were significantly lower in alcoholic patients than in healthy controls or patients with nonalcoholic liver disease. In alcoholic patients 2-keto[1-14C]isocaproic acid decarboxylation was impaired in the presence of normal conventional and quantitative liver function as assessed by aminopyrine breath test and galactose elimination capacity, indicating that 2-keto[1-14C]isocaproic acid decarboxylation does not simply reflect decreased functional liver mass. We conclude that mitochondrial function as reflected by 2-keto[1-14C]isocaproic acid decarboxylation is impaired in chronic alcoholic patients. The functional impairment is specific for excessive ethanol consumption and not a reflection of decreased global liver function or the presence of cirrhosis. 2-Keto[1-14C]isocaproic acid decarboxylation could thus be useful as a marker of excessive ethanol consumption.

Adult↗
PubMed1996

Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin.

We previously reported the induction of calcium-dependent calcium release and depolarization of membrane potential of cardiac mitochondria from rats treated chronically (13 weeks) with doxorubicin. The fact that this was inhibited by cyclosporine A and ruthenium red suggests induction of the mitochondrial permeability transition and calcium cycling. The objective of this investigation was to characterize the cumulative dose-dependent interference with mitochondrial calcium transport by doxorubicin and to assess whether alteration of mitochondrial calcium regulation is manifested as an increased sensitivity to calcium-induced injury to cardiomyocytes isolated from rats exposed in vivo. Mitochondria or cardiomyocytes were isolated from rats treated with 2 mg/kg/week doxorubicin s.c. for 1-9 weeks. Mitochondria isolated from hearts of doxorubicin-treated rats exhibited a dose-dependent increase in sensitivity to calcium-induced calcium release and membrane depolarization, both of which were inhibited by cyclosporine A. Cardiomyocytes isolated from rats treated for 6 weeks with doxorubicin expressed an increased sensitivity to calcium-induced cell killing. The calcium intolerance was prevented by adding either cyclosporine A or ruthenium red to block mitochondrial calcium cycling. These data demonstrate that doxorubicin treatment in vivo causes: (1) a dose-dependent interference with mitochondrial calcium transport and calcium-dependent regulation of membrane potential indicative of induction of the mitochondrial permeability transition, and (2) an increased sensitivity to calcium-induced loss of cell viability. The fact that blocking mitochondrial calcium cycling protected cardiomyocytes from the calcium intolerance suggests that altered regulation of mitochondrial calcium transport may be a critical event in doxorubicin-induced cardiomyopathy.

Animals↗
PubMed2025

Mitochondrial dysfunction fuels drug resistance in adult T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive. METHODS: We have built up the largest known T-ALL tumor bank, with a median follow-up of 32 months, including our transcriptomic data from 79 newly sequenced tumors that adds to the 54 publicly accessible samples. Computational analyses and a series of functional assays were performed to investigate the molecular links between altered mitochondrial activity and drug resistance. RESULTS: The transcriptomic analysis revealed that down-regulation of mitochondrial activity is a potent driver of ABCB1 activation, a gene strongly associated with multidrug resistance. In tumors with low mitochondrial activity, the impaired fatty acids β-oxidation leads to intracellular lipid accumulation, which is directly involved in ABCB1 activation. Indeed, our data show that lipid neo-synthesis and accumulation promotes the activation of lipogenic transcription factors, liver X receptors (LXRs), which act as drivers of ABCB1 expression. Tumor data analyses confirmed that high ABCB1 expression in tumour samples is indeed associated with reduced mitochondrial gene expression, lipid droplet enrichment, increased tumour aggressiveness, and significantly shorter patient survival. CONCLUSIONS: Our study demonstrates that reduced mitochondrial activity drives multidrug resistance in adult T-ALL via lipid-mediated activation of ABCB1. These findings enhance our understanding of the biology of aggressive T-ALL and provide insight into mechanisms of resistance to conventional chemotherapy. Consequently, we propose that targeting de novo lipogenesis and restricting dietary fats, such as caprylic acid, may help overcome treatment resistance in patients with T-ALL exhibiting low mitochondrial activity. TRIAL REGISTRATION: The clinical trial was registered under the identifiers ChiCTR-ONRC-14004968 and ChiCTR2000031553 at ClinicalTrials.gov.

Adult↗
PubMed1995

Relationship between free iron level and rat liver mitochondrial dysfunction in experimental dietary iron overload.

The concentration of total iron in the hepatic tissue and mitochondria from rats fed a 2.5% carbonyl iron supplemented diet progressively increased up to 40 days, then reached nearly a steady-state. By contrast the level of free iron (desferrioxamine-chelatable) exhibited a transient but significant increase at 40 days of treatment, only in this period of treatment the induction of lipid peroxidation and the resulting mitochondrial abnormalities in calcium transport was observed too. The enhancement of the energy dissipating mitochondrial calcium cycling was found to be associated with a significant decrease of endogenous mitochondrial ATP content. As to the pathophysiological mechanism for hepatocellular injury in iron overload, these results indicated that the transit pool of free iron may play a critical role in initiating organelle dysfunctions, at least in this experimental model of iron overload.

Animals↗
PubMed1996

Oxidative stress and mitochondrial dysfunction in neurodegeneration.

Rapid advances are being made in our understanding of the pathogenesis of neurodegenerative diseases, particularly those in which specific DNA mutations have been identified. beta-amyloid has been shown to induce free radical formation both directly and via an effect on endothelial function. There is presuasive evidence for cytochrome oxidase dysfunction with oxidative stress and damage in the brains of patients with Alzheimer's disease. The confirmation of the complex II inhibitor 3-nitropropionic acid as a toxin model for Huntington's disease, together with the demonstration of reduced mitochondrial function in Huntington's disease caudate, supports the proposition that mutant huntingtin may exert its effect through an abnormality of energy metabolism.

Adult↗
PubMed2026

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.

Aneuploidy↗
PubMed1996

Leber's congenital amaurosis associated with mitochondrial dysfunction.

We report the case histories of two 6-month-old girls, both with young, nonconsanguineous parents, referred to us for suspected blindness. In both cases, Leber's congenital amaurosis was diagnosed. Due to persistently high lactic acid levels in blood, muscle biopsies were taken. Analysis of biopsies revealed that both patients had low levels of complex IV of the mitochondrial respiratory chain; one patient additionally had low levels of complex III. Microscopic and ultrastructural alterations of muscle, typically observed in mitochondrial disorders, were observed only in the second patient. These observations raise the possibility that at least some cases of Leber's congenital amaurosis may be due to alterations in the mitochondrial respiratory chain.

Age of Onset↗
PubMed1986

Mitochondrial dysfunction and spinocerebellar degenerations.

A simplified classification of the spinocerebellar degenerations is proposed. Axonal ataxias include Friedreich's ataxia and other conditions involving, primarily, neurons with very long axons. Multiple system degenerations include the various olivopontocerebellar atrophies and related disorders. Ataxic encephalopathies are diffuse diseases of the nervous system in which ataxia is a prominent clinical feature. Several lines of data suggest that mitochondrial damage is a common mechanism in the spinocerebellar degenerations. Reasonable pathophysiological mechanisms can be invoked, linking mitochondrial damage to the observed pathologies (including the many cases of intermediate on variant forms).

Ataxia↗
PubMed1993

Lactate oxidation for the detection of mitochondrial dysfunction in human skin fibroblasts.

To screen fibroblasts for defects in lactate/pyruvate oxidation, cells were grown to confluence in 25-cm2 flasks, rinsed, and incubated in glucose-free media containing 25 microM L-lactate and 0.1 microCi [D,L-1-14C]lactate. Lactate oxidation was measured as the amount of lactate oxidized in nmol of 14CO2 generated/mg protein/min. Fibroblasts from patients with mitochondrial or peroxisomal disorders had decreased lactate oxidation compared to the control (CON): CON, 1.9 +/- 0.13 nmol/mg/min; neonatal adrenoleukodystrophy (NALD), 0.45 +/- 0.01 (P < 0.001); rhizomelic chondrodysplasia punctata (RCDP), 0.13 +/- 0.002 (P < 0.001); mitochondrial defect of unknown etiology (MIT), 0.77 +/- 0.003 (P < 0.001); pyruvate dehydrogenase (PDH) deficiency, 0.98 +/- 0.02 (P < 0.001). This method is useful for screening fibroblasts for defects in lactate oxidation in patients with mitochondrial or peroxisomal disorders. Confirmation of the site of the defect may then be investigated with specific assays, e.g., PDH, in cellular homogenates: CON, 0.93 +/- 0.02 nmol/mg/min; NALD, 0.55 +/- 0.02; RCDP, 0.44 +/- 0.02; MIT, 0.53 +/- 0.03; PDH deficiency, 0.19 +/- 0.02.

Acidosis, Lactic↗