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 307 records · Page 17Linked to original sources
PubMed2001

Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis.

Several lines of evidence support the notion that cellular energetics are deranged in sepsis, not on the basis of inadequate tissue perfusion, but rather on the basis of impaired mitochondrial respiration and/or coupling; that is, organ dysfunction in sepsis may occur on the basis of cytopathic hypoxia. If this concept is correct, then the therapeutic implications are enormous. Efforts to improve outcome in patients with sepsis by monitoring and manipulating cardiac output, systemic Do2, and regional blood flow are doomed to failure. Instead, the focus should be on developing pharmacologic strategies to restore normal mitochondrial function and cellular energetics.

Adenosine Triphosphate↗
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↗
PubMed2002

Hepatic mitochondrial dysfunction in senescence-accelerated mice: correction by long-term, orally administered physiological levels of melatonin.

Mitochondrial oxidative damage from free radicals may be a factor underlying aging. We investigated whether long-term administration of physiological levels of melatonin, a direct free radical scavenger and indirect antioxidant, influences mitochondrial respiratory activity in liver of senescence-accelerated mice (SAM). Liver was obtained in the middle of dark period of the daily light:dark cycle from SAMP8, a strain of mice prone to accelerated senescence, and from SAMR1, a senescence-resistant strain, at 6 and 12 months of age. Respiratory control index (RCI), adenosine-5-diphosphate (ADP)/O ratio, State 3 respiration and dinitophenol (DNP)-dependent uncoupled respiration exhibited significant age-associated decreases in SAMP8. SAMP8 also showed significant age-associated reductions in respiratory chain complex I and IV activities. No age-related effects were found in these parameters in SAMR1. Daily oral melatonin administration (2 microg/mL of drinking fluid) beginning at 7 months of age significantly increased RCI, State 3 respiration, DNP-dependent uncoupled respiration, and complex I and IV activities in both mouse strains when they were 12 months old. These results reveal age-related reductions in mitochondrial function in SAM mice which are modified by melatonin; the most likely explanation for the corrective actions of melatonin relate to its antioxidative actions in mitochondria and other portions of the cell. The implication of the findings is that melatonin may be beneficial during aging as it reduces the deteriorative oxidative changes in mitochondria and other portions of the cell associated with advanced age.

Adenosine Diphosphate↗
PubMed2002

High glucose-induced oxidative stress and mitochondrial dysfunction in neurons.

The current study examines the association between glucose induction of reactive oxygen species (ROS), mitochondrial (Mt) depolarization, and programmed cell death in primary neurons. In primary dorsal root ganglion (DRG) neurons, 45 mM glucose rapidly induces a peak rise in ROS corresponding to a 50% increase in mean Mt size at 6 h (P<0.001). This is coupled with loss of regulation of the Mt membrane potential (Mt membrane hyperpolarization, followed by depolarization, MMD), partial depletion of ATP, and activation of caspase-3 and -9. Glucose-induced activation of ROS, MMD, and caspase-3 and -9 activation is inhibited by myxothiazole and thenoyltrifluoroacetone (P<0.001), which inhibit specific components of the Mt electron transfer chain. Similarly, MMD and caspase-3 activation are inhibited by 100 microM bongkrekic acid (an inhibitor of the adenosine nucleotide translocase ANT). These results indicate that mild increases in glucose induce ROS and Mt swelling that precedes neuronal apoptosis. Glucotoxicity is blocked by inhibiting ROS induction, MMD, or caspase cleavage by specific inhibitors of electron transfer, or by stabilizing the ANT.

Adenosine Diphosphate↗
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↗
PubMed2000

The beneficial effect of ATP-MgCl(2) on hepatic ischemia/reperfusion-induced mitochondrial dysfunction.

The present study was undertaken to determine whether ATP-MgCl(2) administration in rats could protect hepatic mitochondrial function and improve energy metabolism during hepatic ischemia and subsequent reperfusion. Global hepatic ischemia was produced for 60 min followed by reperfusion. The rats then received 0.5 ml of saline or ATP-MgCl(2) intravenously. In saline-treated ischemic rats, serum alanine-aminotransferase levels peaked at 5 h. The aminotransferase level was significantly reduced in the ATP-MgCl(2) treatment group. The wet weight-to-dry weight ratio of the liver was significantly increased by ischemia/reperfusion. ATP-MgCl(2) treatment minimized the increase in this ratio. The ketone body ratio in blood, which reflects the mitochondrial free NAD(+)/NADH ratio, decreased after ischemia and at 1 h following reperfusion. This decrease was somewhat improved by ATP-MgCl(2) infusion. At 1 and 5 h after reperfusion, mitochondrial monoamine oxidase and glutamate dehydrogenase activities decreased. ATP-MgCl(2) infusion following ischemia restored the lost activities. Hepatic ATP levels in saline-treated rats were found to be 50% lower 5 h following reperfusion; however, treatment with ATP-MgCl(2) resulted in significantly higher ATP levels and energy charge. The accumulation of purine catabolites in ischemic tissues was reduced during reperfusion. ATP-MgCl(2) infusion resulted in accumulation of adenosine in reperfused liver. Mitochondrial lipid peroxidation was elevated in the saline-treated ischemic group, but this elevation was inhibited by ATP-MgCl(2) infusion. The present results lead us to conclude that the amelioration of liver function which occurs with ATP-MgCl(2) infusion following ischemia may be mediated through improvement in ischemia-induced mitochondrial energy metabolism.

Adenine Nucleotides↗
PubMed2002

Mitochondrial dysfunction and the role of the non-specialist laboratory.

Each human cell contains at least 1,000 mitochondria, each containing several copies of mitochondrial DNA. This DNA is tiny compared with the nuclear genome, and its structure and products have been fully elucidated. Whilst oxidative phosphorylation depends on the polypeptides encoded by mitochondrial DNA, it also requires a huge number of nuclear DNA products. Inherited deleterious mutations of mitochondrial DNA leading to inefficient oxidative phosphorylation have been described as 'mitochondrial disorders', with a variety of clinical presentations. When similar clinical presentations occur with no discernible mutation of mitochondrial DNA, histological and biochemical evidence is required for diagnosis. The number of these laboratory-proven inherited mitochondrial disorders is growing. It is also becoming clear that mitochondrial DNA defects can be acquired, the most common cause being therapy with highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV-1) infection. Whilst definitive diagnosis of inherited or acquired mitochrondrial dysfunction requires access to specialist laboratory techniques, routine laboratories have a role to play in the initial investigation and monitoring of these conditions.

Cell Respiration↗
PubMed2002

The A8296G mtDNA mutation associated with several mitochondrial diseases does not cause mitochondrial dysfunction in cybrid cell lines.

Transmitochondrial cybrid cell lines homoplasmic for the A8296G mtDNA transition, a mutation associated with several mitochondrial diseases, have a normal oxidative phosphorylation function, as shown by oxygen consumption, lactate production, respiratory enzyme activities, and growth using galactose as the only source of energy. The synthesis of mitochondrial proteins is also similar in mutant and wild-type cybrids. Our results suggest that the A8296G mutation is a polymorphism and reinforce the necessity of performing functional studies to assess the pathogenicity of mtDNA mutations.

Adenine↗
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↗
PubMed2002

Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production.

Introduction of the constitutively active calcineurin gene into neonatal rat cardiomyocytes by adenovirus resulted in decreased mitochondrial membrane potential (P < 0.05). Infection of H9c2 cells with calcineurin adenovirus resulted in increased superoxide production (P < 0.001). Transgenic mice with cardiac-specific expression of a constitutively active calcineurin cDNA (CalTG mice) exhibit a two- to threefold increase in heart size that progresses to heart failure. We prepared mitochondria enriched for the subsarcolemmal population from the hearts of CalTG mice and transgene negative littermates (control). Intact, well-coupled mitochondria prepared from one to two mouse hearts at a time yielded sufficient material for functional studies. Mitochondrial oxygen consumption was measured with a Clark-type oxygen electrode with substrates for mitochondrial complex II (succinate) and complex IV [tetramethylpentadecane (TMPD)/ascorbate]. CalTG mice exhibited a maximal rate of electron transfer in heart mitochondria that was reduced by approximately 50% (P < 0.002) without a loss of respiratory control. Mitochondrial respiration was unaffected in tropomodulin-overexpressing transgenic mice, another model of cardiomyopathy. Western blotting for mitochondrial electron transfer subunits from mitochondria of CalTG mice revealed a 20-30% reduction in subunit 3 of complex I (ND3) and subunits I and IV of cytochrome oxidase (CO-I, CO-IV) when normalized to total mitochondrial protein or to the adenine nucleotide transporter (ANT) and compared with littermate controls (P < 0.002). Impaired mitochondrial electron transport was associated with high levels of superoxide production in the CalTG mice. Taken together, these data indicate that calcineurin signaling affects mitochondrial energetics and superoxide production. The excessive production of superoxide may contribute to the development of cardiac failure.

Adenosine Diphosphate↗
PubMed2003

Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration.

Excessive generation of nitric oxide (NO) has been implicated in the pathogenesis of several neurodegenerative disorders. Damage to the mitochondrial electron transport chain has also been implicated in these disorders. NO and its toxic metabolite peroxynitrite (ONOO(-)) can inhibit the mitochondrial respiratory chain, leading to energy failure and ultimately cell death. There appears to be a differential susceptibility of brain cell types to NO/ONOO(-), which may be influenced by factors including cellular antioxidant status and the ability to maintain energy requirements in the face of marked respiratory chain damage. Although formation of NO/ONOO(-) following cytokine exposure does not affect astrocyte survival, these molecules may diffuse out and cause mitochondrial damage to neighboring NO/ONOO(-)-sensitive cells such as neurons. Evidence suggests that NO/ONOO(-) causes release of neuronal glutamate, leading to glutamate-induced activation of neuronal NO synthase and generation of further damaging species. While neurons appear able to recover from short-term exposure to NO/ONOO(-), extending the period of exposure results in persistent damage to the respiratory chain and cell death ensues. These findings have important implications for acute infection vs. chronic neuroinflammatory disease states. The evidence for NO/ONOO(-)-mediated mitochondrial damage in neurodegenerative disorders is reviewed and potential therapeutic strategies are discussed.

Animals↗