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Results for “Mitochondrial function”

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PubMed1991

Mitochondrial function in myocardial stunning.

Mitochondrial respiration parameters were studied in mitochondria isolated from normal, ischemic and post-ischemic rabbit hearts. Mitochondrial function was related to tissue content of high energy phosphates (HEP) and cardiac function in the isolated working rabbit heart preparation. It was found that after 10 and 20 mins of global normothermic ischemia followed by 20 mins of Langendorff reperfusion, mitochondrial function and HEP content of the myocardium were not significantly diminished. Myocardial creatine phosphate even showed a significant overshoot as compared to the pre-ischemic condition. When these hearts were allowed to perform work, recovery of cardiac function was incomplete while mitochondrial function and HEP content remained in the normal range. Prolonged ischemia (30 mins) resulted in a significant depression of mitochondrial function and myocardial ATP content during and after ischemia. Recovery of contractile function was severely depressed. These results show that impaired cardiac function after a mild ischemic insult (myocardial stunning) can be associated with near normal mitochondrial function and HEP contents.

Adenosine Triphosphate↗

PubMed2004

Preconditioning improves postischemic mitochondrial function and diminishes oxidation of mitochondrial proteins.

This study examines the hypothesis that ischemic or pharmacologic preconditioning improves postischemic mitochondrial function by attenuating oxidation of mitochondrial proteins. Isolated rat hearts were perfused for 38 min preischemia, followed by 25 min global ischemia and then 60 min reperfusion. Hearts were preconditioned by two episodes of 3 min global ischemia, followed by 2 min of reflow (IP), or by perfusion with 50 micromol/l nicorandil (Nic) for 10 min, followed by 10 min washout. IP and Nic significantly (p <.05) improved postischemic function, which was abolished by bracketing the protocols with 200 micromol/l 5-hydroxydecoanate (5HD) or 300 micromol/l alpha-mercaptopropionylglycine (MPG). After isolation of cardiac mitochondria, the respiratory control index (RCI) was calculated from State 3 and State 4 respiration. Both IP and Nic significantly (p <.05) improved postischemic RCI, which was depressed 71% from preischemic values in control hearts. The protective effects of IP and Nic were partially abolished by bracketing with 5HD or MPG. Furthermore, mitochondria from ischemic hearts had significantly (p <.05) less ability to resist swelling on Ca2+ loading, which was improved by both IP and Nic. By use of an immunoblot technique, carbonyl content of multiple bands of mitochondrial proteins was observed to be elevated after 25 min ischemia, and still elevated by the end of 60 min reperfusion. Both IP and Nic attenuated the increased protein oxidation observed at the end of ischemia. The protective effect of IP was almost completely abolished by MPG and partially by 5HD, which also partially abolished the protective effect of Nic. These studies support the conclusion that one mechanism for enhanced postischemic function in the preconditioned heart is improved mitochondrial function as a result of decreased oxidation of mitochondrial proteins.

Animals↗

PubMed1995

The mitochondrial ClpB homolog Hsp78 cooperates with matrix Hsp70 in maintenance of mitochondrial function.

The mitochondrial heat shock protein Hsp78 is a member of the Hsp104/Clp family with unknown function. Saccharomyces cerevisiae deletion mutants of HSP78 show wild-type like growth. We report that deletion of the HSP78 gene in yeast strains with point mutations in the SSC1 gene (encoding matrix Hsp70) led to loss of mitochondrial DNA, indicating that at least one of the heat shock proteins Hsp78 and mt-Hsp70 is needed to maintain a rho+ state of the mitochondrial genome. Mitochondria isolated from these double mutants had a strongly reduced membrane potential, explaining defects in the rate of preprotein import. The lack of Hsp78 led to aggregation of the mutant mt-Hsp70 while other matrix chaperones stayed soluble. We conclude that Hsp78 is required to keep mutant forms of mt-Hsp70 soluble and suggest a cooperation of Hsp78 and mt-Hsp70 in maintenance of essential mitochondrial functions.

Cell Division↗

PubMed2005

Mitochondrial function and actin regulate dynamin-related protein 1-dependent mitochondrial fission.

Mitochondria display a variety of shapes, ranging from small and spherical or the classical tubular shape to extended networks. Shape transitions occur frequently and include fusion, fission, and branching. It was reported that some mitochondrial shape transitions are developmentally regulated, whereas others were linked to disease or apoptosis. However, if and how mitochondrial function controls mitochondrial shape through regulation of mitochondrial fission and fusion is unclear. Here, we show that inhibitors of electron transport, ATP synthase, or the permeability transition pore (mtPTP) induced reversible mitochondrial fission. Mitochondrial fission depended on dynamin-related protein 1 (DRP1) and F-actin: Disruption of F-actin attenuated fission and recruitment of DRP1 to mitochondria. In contrast, uncoupling of electron transport and oxidative phosphorylation caused mitochondria to adopt a distinct disk shape. This shape change was independent of the cytoskeleton and DRP1 and was most likely caused by swelling. Thus, disruption of mitochondrial function rapidly and reversibly altered mitochondrial shape either by activation of DRP1-dependent fission or by swelling, indicating a close relationship between mitochondrial fission, shape, and function. Furthermore, our results suggest that the actin cytoskeleton is involved in mitochondrial fission by facilitating mitochondrial recruitment of DRP1.

Actins↗

PubMed1982

Hereditary polymyopathy and cardiomyopathy in the Syrian hamster. II. Development of heart necrotic changes in relation to defective mitochondrial function.

The mitochondrial oxidative phosphorylation, calcium and magnesium contents, and swelling-contraction activity were investigated in relation to the progression of the hereditary hamster cardiomyopathy. The assessment was made in animals between 22 and 232 days of age, which were divided into 7 groups according to stage of disease. In 24-day-old hamsters prior to development of heart necrotic changes, the membrane permeability of isolated mitochondria was altered. In 50-day-old animals, at a stage of disease when myocardial cells undergo degeneration, a defect of oxidative phosphorylation resulting from an increase in mitochondrial calcium was demonstrated. With culmination of the heart necrotic changes, at close to 100 days of age, mitochondrial dysfunction and calcium overload were maximal. There was a transient improvement during the healing stage, but the situation deteriorated with the occurrence of circulatory failure. Since the mitochondrial respiratory pattern and calcium overload parallel the cardiac degeneration, it is inferred that the cell energy depletion is a functional consequence of an abnormal calcium influx.

Animals↗

PubMed1998

Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity.

Mitochondrial function and ambulatory activity were monitored after feeding old rats acetyl-L-carnitine (ALCAR). Young (3-5 mo) and old (22-28 mo) rats were given a 1.5% (wt/vol) solution of ALCAR in their drinking water for 1 mo, were sacrificed, and their liver parenchymal cells were isolated. ALCAR supplementation significantly reverses the age-associated decline of mitochondrial membrane potential, as assessed by rhodamine 123 staining. Cardiolipin, which declines significantly with age, is also restored. ALCAR increases cellular oxygen consumption, which declines with age, to the level of young rats. However, the oxidant production per oxygen consumed, as measured by 2',7'-dichlorofluorescin fluorescence levels, is approximately 30% higher than in untreated old rats. Cellular glutathione and ascorbate levels were nearly 30% and 50% lower, respectively, in cells from ALCAR-supplemented old rats than in untreated old rats, further indicating that ALCAR supplementation might increase oxidative stress. Ambulatory activity in young and old rats was quantified as a general measure of metabolic activity. Ambulatory activity, defined as mean total distance traveled, in old rats is almost 3-fold lower than in young animals. ALCAR supplementation increases ambulatory activity significantly in both young and old rats, with the increase being larger in old rats. Thus, ALCAR supplementation to old rats markedly reverses the age-associated decline in many indices of mitochondrial function and general metabolic activity, but may increase oxidative stress.

Acetylcarnitine↗

PubMed1981

The interaction of aging and endurance exercise upon the mitochondrial function of skeletal muscle.

Mitochondrial function was determined in sedentary-control animals, 150, 300 and 720 days of age, and in endurance-trained animals 300 and 720 days of age. The mitochondria were isolated from two regions of the cell of the gastrocnemius-plantaris muscle, subsarcolemmal and intermyofibrillar. State 3 respiration did not change with increasing age in control animals, but endurance training enhanced state 3 respiration in both the 300 and 720 day old trained animals. Age decreased the amount of intermyofibrillar mitochondrial protein, while training increased the mitochondrial protein of both regions of the cell. The decrease in oxidative metabolism in the skeletal muscle resulted from a decrease in mitochondrial protein, not to a decrease on mitochondrial function.

Aging↗

PubMed1997

VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function.

The mitochondrial channel, VDAC, forms large (3 nm in diameter) aqueous pores through membranes. We measured ATP flow (using the luciferin/luciferase method) through these channels after reconstitution into planar phospholipid membranes. In the open state of VDAC, as many as 2 x 10(6) ATP molecules can flow through one channel per second. The half-maximum rate occurs at approximately 75 mM ATP. The permeability of a single channel for ATP is 1.1 x 10(-14) cm3/s (about 1 cm/s after correcting for cross-sectional area), which is 100 times less than the permeability for chloride and 10 times less than that for succinate. Channel closure results in a 50% reduction in conductance, showing that monovalent ions are still quite permeable, yet ATP flux is almost totally blocked. This is consistent with an electrostatic barrier that results in inversion of the selectivity of the channel and could be an example of how large channels selectively control the flow of charged metabolites. Thus VDAC is ideally suited to controlling the flow of ATP between the cytosol and the mitochondrial spaces.

Adenosine Triphosphate↗

PubMed2004

Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder.

BACKGROUND: A growing body of experimental evidence suggests that mitochondrial dysfunction, including alterations in phospholipid metabolism, might be involved in the pathophysiology of affective illnesses, such as depression and bipolar disorder. The purpose of this study was to determine whether the phosphomonoester phosphoethanolamine (PE) and the lipid metabolite choline (Cho), which are known to be altered in depression and bipolar disorder, and/or their precursors/metabolites, might directly affect mitochondrial bioenergetic function in vitro. METHODS: To this end, rates of oxygen consumption in freshly isolated, intact mitochondria were determined polarographically in the presence and absence of PE, Cho, ethanolamine (Etn), glycerophosphoethanolamine (GPE), and glycerophosphocholine (GPC). RESULTS: The data demonstrate that PE and Etn inhibit mitochondrial respiratory activity in a dose-dependent manner, whereas Cho, GPC, and GPE have no measurable effect on bioenergetic function. CONCLUSIONS: This reflects a specific inhibition by Etn and PE on mitochondrial function rather than a more generalized phenomenon induced by similarities in structure between the lipid metabolites. These results also suggest a possible relationship between mitochondrial dysfunction and altered phospholipid metabolism in the brains of patients with depression and bipolar disorder.

Animals↗

PubMed1986

Protective effect of prostaglandin I2 on hepatic mitochondrial function of the preserved rat liver.

Mitochondrial function of the liver is one of the limiting factors in liver preservation. Nowadays, prostaglandin I2 (PGI2) is used as a cytoprotective agent in liver preservation without full understanding its mechanism involved. It is the objective of the present study to evaluate the protective effect of PGI2 on mitochondrial function of the rat liver during hypothermic preservation. Collins' solution was used as a preservation solution and PGI2 was added to it in some experimental groups. Both ischemic and non-ischemic livers were perfused with the preservation solution and preserved under simple hypothermia for 8 hr. Parameters of the mitochondrial function such as respiratory control, oxygen consumption rate in state 3 respiration, ADP/O ratio and the rate of ATP synthesis were decreased significantly after 8 hr hypothermic preservation, even if ischemic injury was not induced prior to preservation. ADP/O ratio, which represents the efficiency of oxidative phosphorylation in mitochondria, was improved significantly (p less than 0.01) when PGI2 was used as a cytoprotective agent. The rate of ATP synthesis, a parameter of energy producing reaction, showed a tendency to be increased by PGI2, but was not significant. It was concluded that hypothermic preservation of the rat liver is associated with the deterioration of the mitochondrial function and PGI2 has a favorable effect on the impaired ADP/O ratio of oxidative phosphorylation in mitochondria.

Adenosine Triphosphate↗

PubMed2007

Brain mitochondrial dysfunction in aging: conditions that improve survival, neurological performance and mitochondrial function.

Mice with (a) high spontaneous neurological activity, or subjected to (b) moderate exercise or (c) dietary supplemented with high doses of vitamin E from 28 weeks of age to senescence (76 wk of age), showed an increased survival and a retardation in the development of the neurological deficits associated to aging. During aging there was an increase in dysfunctional brain mitochondria, characterized by an increased content of oxidation products and by a diminished functional activity. The mitochondrial oxidative damage observed in adult (52 wk) and senescent mice (76 wk) was partially ameliorated in the groups of animals subject to the mentioned experimental conditions, and this decrease in mitochondrial oxidative damage was related to the improvement in neurological performance. In brain mitochondria, the activities of enzymes that are critical for mitochondrial function (mtNOS, NADH-dehydrogenase, and cytochrome oxidase) decreased progressively during aging and constituted aging markers. Usual clinical recommendations for aged humans, such as increased neurological activity, moderate exercise, and vitamin E supplementation, proved to be effective in increasing mice survival and neurological performances, along with a better mitochondrial function and a lower content of oxidation products.

Aging↗

PubMed2001

Paradoxical effects of copper and manganese on brain mitochondrial function.

Defects in the mitochondrial genome have been associated with Parkinson's and Alzheimer's disease, and apoptosis can be triggered by the presence of energetically compromised mitochondria. Thus, in this study we have examined whether the divalent cations Cu2+ and Mn2+ could influence mitochondrial function in vitro. Mitochondrial electron transport was dose and time dependently reduced by Cu2+ to a greater extent with succinate as a substrate. Following a 60 min preincubation period, Mn2+ dose dependently inhibited electron transport to a greater extent with lactate and malate. In contrast, paradoxical effects were seen following a 5 min preincubation period with Mn2+. Cu2+ dose-dependently reduced NADH-dependent lactate dehydrogenase (LDH) activity, with almost complete inhibition apparent at 10 microM. An initial induction of LDH by 10 microM Mn2+ was partially reversed by higher concentrations of the metal. Cu2+ dose-dependently reduced flavin adenine dinucleotide (FAD)-dependent monoamine oxidase A (MAO-A) activity in a time-independent manner, with an IC50 value approximately 20 microM, whereas Mn2+ had no effect. In conclusion, it is proposed that Cu2+ and Mn2+ have differential effects on nicotinamide adenine dinucleotide (NAD) and FAD-dependent mitochondrial enzymes at the level of the essential cofactors. Cu2+ appears to exert an inhibitory effect on both NAD and FAD-dependent enzymes, but predominantly against the latter, including MAO-A and succinate dehydrogenase. The complex responses to Mn2+ may be due to dose-related effects on the interconversion of NAD and NADH and reversible enzymatic reactions employing this nucleotide cofactor.

2,6-Dichloroindophenol↗

PubMed1979

Protection of mitochondrial function during ischemia by potassium cardioplegia: correlation with ischemic contracture.

The effect of potassium cardioplegia on mitochondrial function was evaluated in the ischemic isolated rat heart. Mitochondrial function as well as adenosine triphosphate (ATP) levels were determined at the initiation of ischemic contracture, at the completion of ischemic contracture, and 20 minutes following contracture completion. Group I received no cardioplegia prior to ischemia, while Group II received potassium cardioplegia prior to the onset of ischemia. The respiratory control index (RCI), which is the primary measure of the intactness of mitochondrial function, was calculated with both a NAD (nicotinamide adenine dinucleotide)-linked substrate and a FAD (flavin adenine dinucleotide)-linked substrate. Potassium cardioplegia significantly delayed ischemic contracture initiation and completion. Although the RCI and ATP levels decreased significantly at successive levels of contracture, there was no difference in the RCI or ATP content between Group I and Group II at contracture initiation or completion. Unlike previous investigations that have used a time-base to examine mitochondrial function and acute cardiac ischemic injury, we correlated mitochondrial function with the measurable physiologic event ischemic contracture. The data indicated that potassium cardioplegia preserved ATP content and mitochondrial function, and that contracture initiation and completion correlate well with specific ATP levels and mitochondrial respiratory control. The relationship between mitochondrial function and ATP content indicates that the beneficial effect of potassium cardioplegia on mitochondrial function may be secondary to the preservation of high-energy phosphate levels which provide energy for mitochondrial maintenance.

Adenosine Triphosphate↗

PubMed2001

Early effects of AZT on mitochondrial functions in the absence of mitochondrial DNA depletion in rat myotubes.

Zidovudine (AZT) is a potent inhibitor of human immunodeficiency virus (HIV) replication. In humans, as well as in animal models, long-term treatment with AZT induces a severe myopathy characterised by structural and functional alterations of mitochondria associated with depletion of mitochondrial DNA (mtDNA). In the present work, we compared the effects induced by AZT on mitochondria upon short- or long-term treatments of cultured rat myotubes. Morphological alterations were investigated by electron microscopy, and mtDNA depletion and deletions were analysed by Southern blot. Mitochondrial membrane potential was determined after JC-1 staining by laser-scanning confocal microscopy in whole cells, and by flow cytometry in isolated muscle mitochondria. We found that the early effects of AZT on mitochondrial functions were a marked, yet reversible reduction in mitochondrial membrane potential, in the absence of any effect on mtDNA. The long-term treatment, in addition to mitochondrial membrane potential alterations, induced morphological changes in mitochondria, and a remarkable reduction in the amount of mtDNA, without any significant evidence of mtDNA deletions. In both treatments, a block of the spontaneous contraction of myotubes was observed. To study in more detail the early effects induced by AZT, the ability of the drug to interact with cardiolipin, an important component of internal mitochondrial membrane, was investigated by atomic force microscopy (AFM) in an artificial membrane model system. The results suggest that the primary effects of AZT may be related to a physical interference with the membrane structure leading to a consequent modification of its physical characteristics.

Animals↗

PubMed2003

Inhibition of the alpha-ketoglutarate dehydrogenase complex alters mitochondrial function and cellular calcium regulation.

Mitochondrial dysfunction occurs in many neurodegenerative diseases. The alpha-ketoglutarate dehydrogenase complex (KGDHC) catalyzes a key and arguably rate-limiting step of the tricarboxylic acid cycle (TCA). A reduction in the activity of the KGDHC occurs in brains and cells of patients with many of these disorders and may underlie the abnormal mitochondrial function. Abnormalities in calcium homeostasis also occur in fibroblasts from Alzheimer's disease (AD) patients and in cells bearing mutations that lead to AD. Thus, the present studies test whether the reduction of KGDHC activity can lead to the alterations in mitochondrial function and calcium homeostasis. alpha-Keto-beta-methyl-n-valeric acid (KMV) inhibits KGDHC activity in living N2a cells in a dose- and time-dependent manner. Surprisingly, concentration of KMV that inhibit in situ KGDHC by 80% does not alter the mitochondrial membrane potential (MMP). However, similar concentrations of KMV induce the release of cytochrome c from mitochondria into the cytosol, reduce basal [Ca(2+)](i) by 23% (P<0.005), and diminish the bradykinin (BK)-induced calcium release from the endoplasmic reticulum (ER) by 46% (P<0.005). This result suggests that diminished KGDHC activities do not lead to the Ca(2+) abnormalities in fibroblasts from AD patients or cells bearing PS-1 mutations. The increased release of cytochrome c with diminished KGDHC activities will be expected to activate other pathways including cell death cascades. Reductions in this key mitochondrial enzyme will likely make the cells more vulnerable to metabolic insults that promote cell death.

Calcium↗

PubMed1978

Pharmacological protection of mitochondrial function in hypoxic heart muscle: Effect of verapamil, propranolol, and methylprednisolone.

Experiments were undertaken to determine if drugs (verapamil, propranolol, and methylprednisolone sodium saccinate) that protect the fine ultrastructure of heart muscle against damage caused by hypoxia, protect mitochondrial function. Mitochondrial function was assessed in terms of oxidative phosphorylating and Ca2 +-accumulating activities. Isolated rabbit hearts were used, and hypoxic conditions induced by reducing the perfusate PO2 from 80.8 to 0.80 kPa (600 to 6 mmHg). The drugs were either added at the start of the hypoxic perfusion or (verapamil and propranolol) the rabbits were pretreated with them. Verapamil, propranolol and, to a lesser extent, methylprednisolone sodium succinate, provided protection evidenced by the maintainance of near normal mitochondrial oxidative phosphorylating and Ca2 +-accumulating activities after 60 min hypoxic perfusion. When added directly to mitochondria isolated from hypoxic-perfused muscle, the drugs had no effect.

Animals↗

PubMed2001

Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons.

Ethanol impairs insulin-stimulated survival and mitochondrial function in immature proliferating neuronal cells due to marked inhibition of downstream signaling through P13 kinase. The present study demonstrates that, in contrast to immature neuronal cells, the major adverse effect of chronic ethanol exposure (50 mM) in post-mitotic rat cerebellar granule neurons is to inhibit insulin-stimulated mitochondrial function (MTT activity, MitoTracker Red fluorescence, and cytochrome oxidase immunoreactivity). Ethanol-impaired mitochondrial function was associated with increased expression of the p53 and CD95 pro-apoptosis genes, reduced Calcein AM retention (a measure of membrane integrity), increased SYTOX Green and propidium iodide uptake (indices of membrane permeability), and increased oxidant production (dihydrorosamine fluorescence and H2O2 generation). The findings of reduced membrane integrity and mitochondrial function in short-term (24 h) ethanol-exposed neurons indicate that these adverse effects of ethanol can develop rapidly and do not require chronic neurotoxic injury. A role for caspase activation as a mediator of impaired mitochondrial function was demonstrated by the partial rescue observed in cells that were pre-treated with broad-spectrum caspase inhibitors. Finally, we obtained evidence that the inhibitory effects of ethanol on mitochondrial function and membrane integrity were greater in insulin-stimulated compared with nerve growth factor-stimulated cultures. These observations suggest that activation of insulin-independent signaling pathways, or the use of insulin sensitizer agents that enhance insulin signaling may help preserve viability and function in neurons injured by gestational exposure to ethanol.

Amino Acid Chloromethyl Ketones↗

PubMed2000

Effect of weight reduction, obesity predisposition, and aerobic fitness on skeletal muscle mitochondrial function.

We used (31)P magnetic resonance spectroscopy to measure maximal mitochondrial function in 12 obesity-prone women before and after diet-induced weight reduction and in 12 matched, never-obese, and 7 endurance-trained controls. Mitochondrial function was modeled after maximum-effort plantar flexion from the phosphocreatine recovery time constant (TC(PCr)), the ADP recovery time constant (TC(ADP)), and the rate of change in PCr during the first 14 s of recovery (OxPhos). Weight reduction was not associated with a significant change in mitochondrial function by TC(PCr), TC(ADP), or OxPhos. Mitochondrial function was not different between postobese and never-obese controls by TC(PCr) [35.1 +/- 2.5 (SE) vs. 34.6 +/- 2.5 s], TC(ADP) (22.9 +/- 1.8 vs. 21.2 +/- 1.8 s), or OxPhos (0.26 +/- 0. 03 vs. 0.25 +/- 0.03 mM ATP/s), postobese vs. never-obese, respectively. However, TC(ADP) was significantly faster (14.5 +/- 2. 3 s), and OxPhos was significantly higher (0.38 +/- 0.04 mM ATP/s) in the endurance-trained group. These results suggest that maximal mitochondrial function is not impaired in normal-weight obesity-prone women relative to their never-obese counterparts but is increased in endurance-trained women.

Adult↗