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PubMed1997

Cardiac mitochondrial dysfunction and DNA depletion in children with hypertrophic cardiomyopathy.

Abnormalities in specific mitochondrial respiratory enzymes and DNA (mtDNA) have been reported in cardiomyopathy. In this study, we report 4 cases of severe hypertrophic cardiomyopathy (HCM) in which specific cardiac mitochondrial enzyme activity defects were found, including complex I (n = 2), complex III (n = 2), complex IV (n = 2) and complex V (n = 1). Other abnormalities were also noted including a marked depletion of mtDNA (n = 1) and decreased content of subunit 2 of cytochrome c oxidase (n = 1). None of the mtDNA point mutations and common deletions previously found in association with cardiomyopathy were detected in these patients. These data indicate that specific respiratory enzyme activity defects are frequently present in HCM. Also, our finding of a marked depletion of mtDNA in 1 patient suggests that cardiac mtDNA depletion, previously unreported in HCM, needs further examination in order to establish whether it plays a primary role in its pathogenesis.

Cardiomyopathy, Hypertrophic↗
PubMed2026

Mitochondrial dysfunction in muscle cells induced by snoring vibrations.

Snoring-related vibrations have been proposed as a pathogenic factor contributing to upper airway muscle dysfunction in patients with obstructive sleep apnea (OSA). To investigate whether exposure to snoring vibration is linked to muscle weakness, we used an in vitro vibration model to examine its effects on mitochondrial homeostasis in L6 muscle cells at 8, 12, 24, and 48 h. The findings were then compared with mitochondrial alterations in the upper airway muscles from snorers and patients with OSA. Proteomic analysis of L6 myoblasts revealed extensive remodeling of the mitochondrial proteome at 8 h, affecting pathways involved in oxidative phosphorylation, protein import, ribosome biogenesis, and RNA processing. Respiratory chain remodeling was subunit-specific, with increased abundance of selected components of Complexes I, IV, and V, including NDUFS4, COX5A, and ATP5PD. However, reductions in spliceosome-associated factors, such as SRSF2 and DDX46, along with alterations in mitochondrial ribosomal proteins, indicated impaired RNA processing and protein synthesis. Furthermore, both proteomic and transcriptomic analyses revealed activation of a mechanosensing-mechanotransduction axis, with early upregulation of integrin subunits and mechanosensitive ion channels, followed by transient activation of focal adhesion signaling. Despite transcriptional upregulation of selected Complex IV subunits Cox5a and Cox6a2, this response was accompanied by accumulation of unspliced pre-mRNA, indicating impaired RNA processing efficiency and a decoupling between transcript and protein levels. Real-time Seahorse assay revealed a collapse of mitochondrial respiration and glycolytic reserve at 8 h. Although mitochondrial oxygen consumption recovered after 48 h, the ability to dynamically upregulate glycolysis remained impaired. In patients, muscle capillarization was impaired, COX activity was reduced, and mitochondrial organization was disrupted. Moreover, transcription of Complex IV subunits COX5A and COX6A2 was, as in vibrated L6 cells, upregulated, suggesting a mismatch between transcript levels and protein expression. We conclude that snoring-induced vibrations are an unrecognized stressor that disrupts mitochondrial homeostasis in muscle by impairing RNA processing, protein synthesis, and mechanotransduction-driven mitochondrial remodeling, leading to transcript-protein uncoupling and likely muscle dysfunction.

Humans↗
PubMed1990

Mitochondrial dysfunction in paracetamol hepatotoxicity: in vitro studies in isolated mouse hepatocytes.

The effect of paracetamol intoxication on mitochondrial function was studied in isolated mouse hepatocytes. Inhibition of cellular respiration as well as a lowering of cellular ATP contents and ATP/ADP ratios was associated with exposure to toxic concentrations of paracetamol. Significantly, inhibition of 3-hydroxybutyrate- and lactate/pyruvate-supported respiration, as well as the reduction in cellular ATP levels and ATP/ADP ratios, preceded the appearance of plasma membrane damage, as assessed by LDH leakage. N-Acetylcysteine reduced the extent of plasma membrane damage induced by paracetamol and protected against the impairment of cellular respiration. This suggests that respiratory dysfunction was a consequence of the oxidation of paracetamol to its reactive metabolite within the liver cell. These findings indicate that paracetamol toxicity results in an impairment of mitochondrial function which precedes the loss of plasma membrane integrity.

Acetaminophen↗
PubMed1997

Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: targets for therapy.

Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor-plasminogen activator inhibitor type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride ([Au(DPPE)2]Cl), CdCl2 and the mitochondrial inhibitors rhodamine-123 (Rh123), dequalinium chloride (DeCH), tetraphenylphosphonium (TPP), and ethidium bromide (EtBr) and with lower constitutive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were additionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poor reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-Sla was similar to HeLa, but DNA-bound platinum was much lower than for the parent cell line. The mitochondria of CI-80-13S and HeLa-S1a showed altered morphology and were fewer in number than those of JAM and HeLa. In both models, CDDP resistance was associated with less platinum accumulation and with mitochondrial and membrane defects, brought about one case with expression of a protease inhibitor which is implicated in tumor progression. Such markers may identify tumors suitable for treatment with gold phosphine complexes or other mitochondrial inhibitors.

Adenosine Triphosphate↗
PubMed1998

Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux.

We and others have recently shown that loss of the mitochondrial membrane potential (Deltapsi) precedes apoptosis and chemical-hypoxia-induced necrosis and is prevented by Bcl-2. In this report, we examine the biochemical mechanism used by Bcl-2 to prevent Deltapsi loss, as determined with mitochondria isolated from a cell line overexpressing human Bcl-2 or from livers of Bcl-2 transgenic mice. Although Bcl-2 had no effect on the respiration rate of isolated mitochondria, it prevented both Deltapsi loss and the permeability transition (PT) induced by various reagents, including Ca2+, H2O2, and tert-butyl hydroperoxide. Even under conditions that did not allow PT, Bcl-2 maintained Deltapsi, suggesting that the functional target of Bcl-2 is regulation of Deltapsi but not PT. Bcl-2 also maintained Deltapsi in the presence of the protonophore SF6847, which induces proton influx, suggesting that Bcl-2 regulates ion transport to maintain Deltapsi. Although treatment with SF6847 in the absence of Ca2+ caused massive H+ influx in control mitochondria, the presence of Bcl-2 induced H+ efflux after transient H+ influx. In this case, Bcl-2 did not enhance K+ efflux. Furthermore, Bcl-2 enhanced H+ efflux but not K+ flux after treatment of mitochondria with Ca2+ or tert-butyl hydroperoxide. These results suggest that Bcl-2 maintains Deltapsi by enhancing H+ efflux in the presence of Deltapsi-loss-inducing stimuli.

Animals↗
PubMed1991

Effects of prostaglandin E1 on the recovery of ischemia-induced liver mitochondrial dysfunction in rats with cirrhosis.

Interruption of hepatic blood supply for 60 min deteriorated liver mitochondrial respiratory functional indices--that is, respiratory control index (RCI) and the rate of oxygen consumption in state-III respiration (ST III O2). Recovery of ischemia-induced decreases in these functional indices in a saline-administered cirrhotic liver group was retarded compared with that in a normal liver group, and significantly low RCI and ST III O2 persisted 15 min after reperfusion. Prostaglandin E1 (PGE1) did not improve ischemia-induced decreases in RCI and ST III O2 but accelerated the recovery of mitochondrial respiratory function after reperfusion. Adenosine triphosphate (ATP) levels were markedly decreased during ischemia, and retardation of ATP recovery was also observed in rats with cirrhosis. PGE1 improved the recovery of ATP level in rats with cirrhosis. Liver blood flow in the cirrhotic liver was significantly lower than that of the normal liver. PGE1 enhanced liver blood flow. These results indicate that retardation of the recovery of RCI and ST III O2 in the cirrhotic liver might be based on the decrease in tissue blood flow and that agents increasing tissue blood flow might contribute to the acceleration of the recovery of mitochondrial respiratory function.

Adenine Nucleotides↗
PubMed1994

Evidence for mitochondrial dysfunction in Parkinson's disease--a critical appraisal.

There is now considerable evidence to support a defect of the mitochondrial respiratory chain, and complex I in particular, in Parkinson's Disease (PD). However, the site specificity of the defect within the chain, its anatomical selectivity within the brain, and its presence in other tissues still remain controversial. Much of the present confusion surrounding the mitochondrial defect can be dispelled by careful analysis of the available data. The molecular basis of the deficiency and its relevance to the pathogenesis of PD remain unknown. Nevertheless, the complex I deficiency in PD provides a direct biochemical link between the idiopathic disease and the MPTP toxin model. The relationship between the mitochondrial defect and other abnormalities within the PD substantia nigra suggests that a self amplifying cycle of events might be precipitated either by a genetic or environmentally induced abnormality of mitochondrial function or free radical metabolism. Alternatively, a biochemical event separate from these might precipitate a cascade which terminates in complex I dysfunction and free radical formation. An understanding of the molecular basis of the complex I defect in PD and its relationship to other biochemical changes will provide important insight into the potential chain of events that lead to dopaminergic cell death in PD.

Animals↗
PubMed2025

Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's and Parkinson's disease using Polygenic Risk Scores and Mendelian Randomization.

INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates. METHODS: Using GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR). RESULTS: Across the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk. DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.

Alzheimer’s disease↗
PubMed1998

Mitochondrial dysfunction in Parkinson's disease.

This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.

Cell Nucleus↗
PubMedDate not supplied

Cardiac mitochondrial dysfunction in Leigh syndrome.

An infant with Leigh syndrome and associated cardiomyopathy is described. Abnormal activities of mitochondrial respiratory complexes III and V and a change in mtDNA at nt 8993 were detected in heart and skeletal muscle but not in liver.

Cardiomyopathies↗
PubMed1996

Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart.

The objective of this study was to determine whether a defect in mitochondrial respiratory function accompanies the development of diabetic cardiomyopathy. The hypothesis tested in this study is that a decrease in Ca2+ uptake into mitochondria may prevent the stimulation of Ca(2+)-sensitive matrix dehydrogenases and the rate of ATP synthesis. Streptozotocin (55 mg/kg)-induced diabetic rats were used as a model of insulin-dependent diabetes mellitus. Hearts from 4-wk diabetic rats had basal heart rates and rates of contraction and relaxation similar to control. Isoproterenol caused a similar increase in the rate of contraction in diabetic and control hearts, whereas the peak rate of relaxation was reduced in diabetic hearts. Mitochondrial Ca2+ uptake was reduced in mitochondria from diabetic hearts after 2 wk of diabetes. Na(+)-induced Ca2+ release was unchanged. State 3 respiration rate was depressed in mitochondria from diabetic rats only when the respiration was supported by the substrate of a Ca(2+)-regulated matrix enzyme. The pyruvate dehydrogenase activity was reduced in diabetic mitochondria compared with that of control. It was concluded that mitochondria from diabetic hearts had a decreased capacity to upregulate ATP synthesis via stimulation of Ca(2+)-sensitive matrix dehydrogenases. The impairment in the augmentation of ATP synthesis rate accompanies a decreased rate of relaxation during increased work load.

Animals↗
PubMed2026

Proteomic signatures of mitochondrial dysfunction associated with atrial fibrillation in goats.

Atrial fibrillation (AF) increases energy demand in atrial myocytes, yet the mitochondrial mechanisms underlying this stress remain poorly defined. Using previously published proteomic data from left atrial tissue of AF and sham-operated goats, we performed organelle-specific bioinformatic analyses of the mitochondrial fraction. Over-representation and consensus pathway analyses consistently highlighted enrichment of oxidative phosphorylation (OXPHOS) subunits. Gene set enrichment and network analyses implicated Heat Shock Protein Family A Member 9 (HSPA9) as a potentially central regulatory hub coordinating the dysregulation of Complex I and III subunits, with 69% of regulatory relationships showing pathway concordance. These results indicate a coordinated, system-wide mitochondrial adaptation in AF, integrating energy production, proteostasis, and respiratory chain regulation.

Animals↗
PubMed1995

Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers.

In several models of lymphocyte apoptosis, two alterations of mitochondrial function precede advanced DNA fragmentation: (1) a reduction of mitochondrial transmembrane potential (delta psi m) and (2) an increase in mitochondrial generation of superoxide anion. Here we show that two fluorochromes allow for the identification of analogous mitochondrial perturbations in circulating T lymphocytes from human immunodeficiency virus (HIV)-1+ donors. The first among these fluorochromes, the cationic lipophilic dye DiOC6(3), measures delta psi m; the second marker, hydroethidine (HE), is nonfluorescent, unless it is oxidized by superoxide anions to the product ethidium (Eth). CD4+ or CD8+ cells from clinically asymptomatic HIV-1 carriers contain a significantly elevated percentage of cells endowed with enhanced HE --> Eth conversion and/or reduced DiOC6(3) uptake as compared with normal controls. Phenotypic characterization of (HE --> Eth)high cells from HIV+ donors shows that these cells possess a low delta psi m, thus demonstrating a functional alteration of mitochondria. In addition, (HE --> Eth)high cells display a reduced incorporation of the cardiolipin-specific dye nonyl-acridine orange (NAO), showing a structural defect of the cardiolipin-containing inner mitochondrial membrane. Control experiments involving rotenone, an inhibitor of the respiratory chain complex I, indicate that the reactive oxygen species responsible for HE --> Eth conversion is generated during mitochondrial electron transport. In synthesis, it appears that mitochondrial alterations occur in a significant percentage of circulating T lymphocytes from HIV-1 carriers. The extent of delta psi m reduction, as determined ex vivo, correlates with the frequency of cells undergoing DNA fragmentation after overnight in vitro culture. These observations may be important for the understanding and for the direct ex vivo quantitation of HIV-triggered lymphocyte destruction.

Acquired Immunodeficiency Syndrome↗
PubMed1980

Mitochondrial dysfunction of the liver and hypoglycemia in hemorrhagic shock.

In this study, the aim was to characterize the relationship of hypoglycemia to hepatic mitochondrial function and hepatic glycogen stores in late hemorrhagic shock. With the use of a modified Wiggers' model of hemorrhagic shock, blood glucose, hepatic mitochondrial function and hepatic glycogen were measured when reinfusion of 60 per cent of the shed blood was required to maintain the blood pressure at 30 millimeters of mercury. Defective mitochondrial energy-linked metabolism was more sensitively detected with isocitrate as substrate than with alpha-ketoglutarate, succinate or malate. The correlation between the blood and hepatic glycogen content was only 0.43 when oxidative phosphorylation was coupled. When oxidative phosphorylation with isocitrate was uncoupled, the relationship between blood glucose and hepatic glycogen was exponential, with a correlation of 0.91. The results suggest that defective energy-linked mitochondrial function impairs gluconeogenesis and that hypoglycemia occurs when oxidative phosphorylation becomes uncoupled and hepatic glycogen stores are subsequently depleted.

Animals↗
PubMed1999

Mitochondrial dysfunction in skeletal muscle of children with cardiomyopathy.

OBJECTIVES: This study sought to examine skeletal muscle of children with cardiomyopathy (CM) for changes in mitochondrial enzyme activities and in mitochondrial DNA (mtDNA). BACKGROUND: Heart mitochondrial enzymatic activity defects have been often found in dilated and hypertrophic CM. The defects primarily involve the activities of the electron transport system and oxidative phosphorylation pathway including respiratory complexes I, III, IV, and V. METHODS: Skeletal muscle biopsies of 8 children with CM were examined for specific mitochondrial enzyme activities, mtDNA copy number and the presence of pathogenic mutations and deletions in mtDNA. RESULTS: A marked deficiency in specific mitochondrial enzyme activities was found in 6 of 8 patients in skeletal muscle as well as in 2 of 3 hearts of those in whom cardiac tissue was available. Specific activity defects were found in complex I (2 cases), complex III (5 cases), complex IV (3 cases), and complex V (4 cases). Complex II and citrate synthase activities were unaffected. None of the previously reported pathogenic mutations associated with CM were detected, nor was there any evidence of mtDNA depletion. The incidence of defective respiratory complex activities in skeletal muscle was similar to the incidence of defective complex activities previously reported in cardiac tissue. CONCLUSIONS: Mitochondrial analysis of skeletal muscle is warranted in the overall clinical evaluation of children with CM, and particularly before consideration for cardiac transplantation.

Adolescent↗
PubMed1996

Role of nitric oxide and superoxide anion in leukotoxin-, 9,10-epoxy-12-octadecenoate-induced mitochondrial dysfunction.

The present study was carried out to explore the involvement of nitric oxide (NO) and superoxide anion (O2.-) in Leukotoxin (Lx)-induced suppression of mitochondrial respiration. Glutamate- and succinate-dependent oxygen consumption and cytochrome c oxidase activity were assayed. Lx-induced mitochondrial damage was significantly attenuated by the pretreatment of lung with 4 x 10(-4) M NG-monomethyl-L-arginine (L-NMMA) or 500 units/ml superoxide dismutase (SOD) in ex vivo. However, L-NMMA plus SOD pretreatment showed no additive effect on the recovery of mitochondrial functions. The same assay was performed after the exposure of intact mitochondria to NO containing solution (1.25 x 10(-5) M) or 0.1 mM KO2/18-Crown-6 solution, which generated O2.-(6.4 x 10(-5) M). NO, but not O2.-, significantly inhibited the respiration of isolated mitochondria in vitro. Thus, there were great discrepancies in the involvement of NO and O2.- between ex vivo and in vitro system. Together with the previous reports, these facts suggested that the mechanisms by which NO and O2.- probably from vascular constituent cells inhibit mitochondrial respiration function of isolated perfused rat lung may not be simply due to their direct reactions with mitochondrial electron transport chain components, but may rely on the formation of peroxynitrite, and/or peroxynitrite-derived oxidants.

Animals↗