SEARCH · PubMed Health

Results for “Mitochondrial function”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 361 records · Page 20Linked to original sources

PubMed2005

The relevance of mitochondrial membrane topology to mitochondrial function.

This review summarizes recent findings from electron tomography about the three-dimensional shape of mitochondrial membranes and its possible influence on a range of mitochondrial functions. The inner membrane invaginations called cristae are pleomorphic, typically connected by narrow tubular junctions of variable length to the inner boundary membrane. This design may restrict intra-mitochondrial diffusion of metabolites such as ADP, and of soluble proteins such as cytochrome c. Tomographic images of a variety of mitochondria suggest that inner membrane topology reflects a balance between membrane fusion and fission. Proteins that can affect cristae morphology include tBid, which triggers cytochrome c release in apoptosis, and the dynamin-like protein Mgm1, involved in inter-mitochondrial membrane fusion. In frozen-hydrated rat-liver mitochondria, the space between the inner and outer membranes contains 10-15 nm particles that may represent macromolecular complexes involved in activities that span the two membranes.

Animals↗

PubMed2003

Highly active antiretroviral therapy (HAART)-associated lactic acidosis: in vitro effects of combination of nucleoside analogues and protease inhibitors on mitochondrial function and lactic acid production.

Lactic acidosis is a rare but potentially life-threatening and poorly understood sequelae among HIV-infected patients on highly active antiretroviral therapy (HAART). Mitochondrial DNA depletion and inhibition of respiratory complexes have been hypothesized to be involved in HAART-associated lactic acidosis. Although mitochondrial toxicity and increased plasma lactates are associated with long-term exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI), reports of lactic acidosis are now emerging among HIV-infected patients exposed to combination therapy that includes not only NRTI but also protease inhibitors (PI). We therefore investigated the effects of clinically relevant NRTI and PI combinations on mitochondrial membrane potential, uncoupling of mitochondrial respiration from oxidative phosphorylation and lactic acid production. Our study demonstrated that treatment of HepG2 cells with a combination of nucleoside analogues and PI, decreased mitochondrial membrane potential (delta psi m) within 24 hr, followed by increased lactic acid production after 9 days of treatment. However, loss of delta psi m and increased lactates were not associated with mitochondrial uncoupling or ATP production. Our findings suggested that not only NRTI but also PI are capable of increasing lactic acid production in vitro, and probably involve early biochemical changes in mitochondrial function such as loss of mitochondrial membrane potential.

Acidosis, Lactic↗

PubMed1998

Cyc2p is required for maintaining ionic stability and efficient cytochrome c import and mitochondrial function in Saccharomyces cerevisiae.

A previous study demonstrated that. Cyc2p from Saccharomyces cerevisiae is a mitochondrial protein and that cyc2 mutants contained only approximately 20% of the normal levels of cytochrome c due to a partial deficiency in mitochondrial import of apo-cytochrome c. We report herein that deletion of the entire gene results in defective mitochondrial function, as revealed by diminished growth on media containing nonfermentable carbon sources. This defect is exacerbated in hyper-ionic KCl media and at higher incubation temperatures, but is suppressed on media containing sorbitol, a non-ionic compound. We suggest that Cyc2p serves to maintain the osmotic stability of mitochondria, and its defect is exacerbated by KCl.

Biological Transport↗

PubMed2000

Opening of potassium channels protects mitochondrial function from calcium overload.

Ischemic preconditioning (IPC) protects myocardium from ischemia reperfusion injury by activating mitochondrial K(ATP) channels. However, the mechanism underlying the protective effect of K(ATP) channel activation has not been elucidated. It has been suggested that activation of mitochondrial K(ATP) channels may prevent mitochondrial dysfunction associated with Ca(2+) overload during reperfusion. The purpose of this experiment was to study, in an isolated mitochondrial preparation, the effects of mitochondrial K(ATP) channel opening on mitochondrial function and to determine whether it protects mitochondria form Ca(2+) overload. Mitochondria (mito) were isolated from rat hearts by differential centrifugation (n = 5/group). Mito respiratory function was measured by polarography without (CONTROL) or with a potassium channel opener (PINACIDIL, 100 microM). Different Ca(2+) concentrations (0 to 5 x 10(-7) M) were used to simulate the effect of Ca(2+) overload; state 2, mito oxygen consumption with substrate only; state 3, oxygen consumption stimulated by ADP; state 4, oxygen consumption after cessation of ADP phosphorylation; respiratory control index (RCI: ratio of state 3 to state 4); rate of oxidative phosphorylation (ADP/Deltat); and ADP:O ratio were measured. PINACIDIL increased state 2 respiration and decreased RCI compared to CONTROL. Low Ca(2+) concentrations stimulated state 2 and state 4 respiration and decreased RCI and ADP:O ratios. High Ca(2+) concentrations increased state 2 and state 4 respiration and further decreased RCI, state 3, and ADP/Deltat. PINACIDIL improved state 3, ADP/Deltat, and RCI at high Ca(2+) concentrations compared to CONTROL. Pinacidil depolarized inner mitochondrial membrane, as evidenced by decreased RCI and increased state 2 at baseline. Depolarization may decrease Ca(2+) influx into mito, protecting mito from Ca(2+) overload, as evidenced by improved state 3 and RCI at high Ca(2+) concentrations. The myocardial protective effects resulting from activating K(ATP) channels either pharmacologically or by IPC may be the result of protecting mito from Ca(2+) overload.

Animals↗

PubMed2003

Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis.

During apoptosis, the permeabilization of the mitochondrial outer membrane allows the release of cytochrome c, which induces caspase activation to orchestrate the death of the cell. Mitochondria rapidly lose their transmembrane potential (Delta Psi m) and generate reactive oxygen species (ROS), both of which are likely to contribute to the dismantling of the cell. Here we show that both the rapid loss of Delta Psi m and the generation of ROS are due to the effects of activated caspases on mitochondrial electron transport complexes I and II. Caspase-3 disrupts oxygen consumption induced by complex I and II substrates but not that induced by electron transfer to complex IV. Similarly, Delta Psi m generated in the presence of complex I or II substrates is disrupted by caspase-3, and ROS are produced. Complex III activity measured by cytochrome c reduction remains intact after caspase-3 treatment. In apoptotic cells, electron transport and oxygen consumption that depends on complex I or II was disrupted in a caspase-dependent manner. Our results indicate that after cytochrome c release the activation of caspases feeds back on the permeabilized mitochondria to damage mitochondrial function (loss of Delta Psi m) and generate ROS through effects of caspases on complex I and II in the electron transport chain.

Amino Acid Chloromethyl Ketones↗

PubMed2004

A novel mechanism of regulation of cardiac contractility by mitochondrial functional state.

It is generally considered that mitochondria regulate cardiac cell contractility by providing ATP for cellular ATPases and by participating in Ca2+ homeostasis. However, other possible mechanisms by which mitochondria can influence contractility have been largely overlooked. Here, we demonstrate that inhibition of the mitochondrial electron transport chain strongly increases Ca2+-dependent and independent isometric force development in rat ventricular fibers with selectively permeabilized sarcolemma. This effect is unrelated to the ATP-generating activity of mitochondria or Ca2+ homeostasis. Furthermore, various conditions that increase K+ accumulation in the mitochondrial matrix (activation of ATP- or Ca2+-dependent K+ channels as well as inhibition of the K+ efflux pathway via the K+/H+ exchanger) induce a similar mechanical response. Modulators of mitochondrial function that augment isometric force also cause swelling of mitochondria in the vicinity of myofibrils in situ, as shown by confocal microscopy. Osmotic compression of intracellular structures abolishes the effect of mitochondria-induced force modulation, suggesting a mechanical basis for the interaction between the organelles. These findings suggest a novel mechanism for cellular regulation of myofibrillar function, whereby increases in mitochondrial volume can impose mechanical constraints inside the cell, leading to an increase in force developed by myofibrils.

Adenosine Triphosphate↗

PubMed1992

Age-related decrease in respiratory muscle mitochondrial function in rats.

The purpose of this study was to elucidate the effects of aging on diaphragmatic mitochondrial function. Diaphragm mitochondria were prepared from specific pathogen-free rats aged 7 wk (n = 7), 35 wk (n = 7), and 55 wk (n = 7). The activities of various portions of the mitochondrial electron transport chain, i.e., complexes I, II, III, and IV, were measured enzymatically. The specific activities of complex I decreased significantly (P less than 0.01) in 35-wk-old rats (726 +/- 90 nmol/min/mg protein) compared with 7-wk-old rats (1,018 +/- 121), and the decrease was more remarkable in 35-wk-old rats (565 +/- 64; P less than 0.01 versus 35-wk-old). The activities of complex IV also decreased significantly (P less than 0.01) in 55-wk-old rats (1,222 +/- 191) compared with 7-wk-old rats (1,797 +/- 208); however, no significant changes in complex IV activities between 7-wk-old rat and 35-wk-old rats were observed. In contrast, the activities of complex II and III were not affected by aging. Limb muscle, heart, and liver mitochondria were also prepared from the same rats. The same tendency was observed in limb muscle mitochondria; however, in heart and liver mitochondria, activities of all four complexes were not changed in rats of all age groups. These results indicate that vulnerability of mitochondrial electron transport chain to aging differs from organ to organ and that it also differs from portion to portion in the electron transport chain and the most vulnerable site was complex I.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed2003

Profiling genes related to mitochondrial function in mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Since mitochondrial dysfunction plays an important role in the pathogenesis of dopaminergic neurodegeneration in Parkinson's disease, we determined the expression of genes related to mitochondrial function in the substantia nigra of mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a cDNA array. MPTP treatment significantly depleted striatal dopamine, but did not result in apparent neuronal loss in the substantia nigra at 3 and 18 days post-treatment. We also examined changes in genes in the hypothalamus, a region containing dopaminergic neurons that are relatively resistant to MPTP. Finally, we confirmed those genes identified by microarrays as differentially expressed in the substantia nigra but not in the hypothalamus using in situ hybridization. Our results demonstrated that MPTP significantly changed the expressions of six genes in nigral neurons, four of which were related to the mitochondrial electron transport chain: the NADH-ubiquinone oxidoreductase 13 kDa B subunit, the NADH-ubiquinone oxidoreductase MNLL subunit, cytochrome c, and the cytochrome c oxidase Va subunit. Two other differentially expressed genes were the dihydropyridine-sensitive L-type calcium channel alpha-2 subunit precursor and type III alpha-1 procollagen. None of these six genes are encoded by mitochondrial DNA. The potential significance of these gene alterations in the context of Parkinson's disease is discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2007

Brain nitric oxide synthases and mitochondrial function.

Nitric oxide is a small signaling molecule, which may act as a neurotransmitter and neuromodulator, exerting a regulatory effect on neuronal function. It can diffuse from its site of synthesis to different intra and extracellular compartments, being therefore present in the pre-synaptic, synaptic and post-synaptic spaces. Recently, a NOS located in the mitochondria (mtNOS) has been observed in different brain regions, responsible for the production of NO in these organelles and identified as nNOS. A regulatory effect of NO on mitochondrial function was described in brain mitochondria, where NO acts mainly by inhibiting cytochrome oxidase activity. Hippocampal mitochondrial dysfunction and decreased mtNOS activity and expression were reported in association with ultrastructural damage in an experimental model of hepatic encephalopathy. Enriched environment exposure preserved the aged animals from spatial cognition impairment; also environment and training modulated neuronal plasticity in pre-pubertal rats through NO-dependent mechanisms. In addition, brain cortical mitochondrial respiration and mtNOS activity and expression were analyzed as function of age. Mitochondrial NO production showed a decreasing tendency as a function of age. These results are in accordance with the protein expression analyzed by Western Blot of mitochondrial fractions which was 6.5 times higher in 1 month aged rats as compared with 14 old animals. Concomitant with these results, a clear increasing oxygen uptake tendency in state 3 respiration was observed, meanwhile only a slight increase was observed in state 4. All these results seems to be clearly related with the reversible and concentration-dependent attenuation of the respiratory chain by NO.

Aging↗

PubMed1990

ATP depletion and mitochondrial functional loss during ischemia in slow and fast heart-rate hearts.

In the present study, isolated dog and rat hearts were perfused in the Langendorff mode with Krebs bicarbonate buffer in the absence and presence of 10(-5) M oligomycin. The perfusion protocols employed allowed tissue pH to drop during subsequent ischemic incubations essentially as it would in blood-perfused hearts. Tissue pH, ATP, lactate, and mitochondrial respiratory function were measured during the course of subsequent zero-flow ischemic incubations. The adenosinetriphosphatase (ATPase) activities attributable to both mitochondrial and nonmitochondrial ATPases in sonicated heart homogenates and the actomyosin ATPase in isolated cardiac myofibrils were measured in both species. Consistent with earlier results with a different model in which tissue pH was buffered during the ischemic incubations [W. Rouslin, J. L. Erickson, and R. J. Solaro. Am. J. Physiol. 250 (Heart Circ. Physiol. 19): H503-H508, 1986], the inhibition of the mitochondrial ATPase in situ by oligomycin markedly slowed both tissue ATP depletion and the loss of mitochondrial function during ischemia in the dog. However, oligomycin had only a very small and transient effect on ATP depletion and mitochondrial function in the rat. This was apparently so because of the fivefold higher rate of glycolytic ATP production as well as the nearly threefold higher total nonmitochondrial ATPase activity of ischemic rat compared with ischemic dog heart. These results suggest that although the inhibition of the mitochondrial ATPase makes a major contribution to ATP conservation in ischemic dog heart, it makes only a very small contribution in rat.

Adenosine Triphosphatases↗

PubMed1981

Changes in mitochondrial function by lipid peroxidation and their inhibition by biscoclaurin alkaloid.

During in vitro investigation of changes in mitochondrial function accompanying lipid peroxidation, it was found that cepharanthine, a biscoclaurin alkaloid, protects against such change. Results obtained were as follows: (1) Fe2+ induces lipid peroxidation of isolated mitochondria, resulting in diminished oxidative phosphorylation. (2) This diminishment largely depends on deterioration of ion compartmentation of the membrane and an increase in latent ATPase activity. (3) The Fe2+-induced deterioration in ion compartmentation is inhibited by cepharanthine. (4) Cepharanthine inhibits the mitochondrial lipid peroxidation induced by Fe2+. (5) Cepharanthine inhibits the lipid peroxidation of soybean lecithin liposomes by 60Co-irradiation.

Adenosine Triphosphatases↗

PubMed2006

Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney.

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg x kg(-1) x day(-1); Enal), or a NO synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg x kg(-1) x day(-1)), or both (Enal+L-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by L-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. L-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by L-NAME cotreatment. In Enal, kidney mitochondria H(2)O(2) production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by L-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Lipid replacement/antioxidant therapy as an adjunct supplement to reduce the adverse effects of cancer therapy and restore mitochondrial function.

The most common complaints of cancer patients undergoing chemo- or radiotherapy are fatigue, nausea, vomiting, malaise, diarrhea and headaches. These adverse effects are thought to be due to damage of normal tissues during the course of therapy. In addition, recent evidence indicates that fatigue is related to reduced mitochondrial function through loss of efficiency in the electron transport chain caused by membrane oxidation, and this occurs during aging, in fatiguing illnesses and in cancer patients during cytotoxic therapy. Lipid Replacement Therapy administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage to normal tissues, restore mitochondrial and other cellular membrane functions and reduce the adverse effects of cancer therapy. Recent clinical trials using patients with chronic fatigue have shown the benefit of Lipid Replacement Therapy plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue by protecting mitochondrial and other cellular membranes from oxidative and other damage. In cancer patients a placebo-controlled, cross-over clinical trial using Lipid Replacement Therapy plus antioxidants demonstrated that the adverse effects of chemotherapy can be reduced in 57-70% of patients. Dietary use of unoxidized membrane lipids plus antioxidants is recommended for patients undergoing cancer therapy to improve quality of life but should not be taken at the same time of day as the therapy.

Antioxidants↗

PubMed1990

Effects of phthalic acid esters on testicular mitochondrial functions in the rat.

Although it is well established that high dose administration of di(2-ethylhexyl) phthalate (DEHP) and its monoester metabolite (MEHP) induces severe testicular atrophy in rats, the mechanisms of this testicular injury is not clear. The present experiment was undertaken to examine the effects of DEHP and MEHP on mitochondrial functions of rat testis. DEHP and di-n-octyl phthalate (DOP), a DEHP isomer which causes less severe testicular injury, did not inhibit the state 3 oxygen consumption up to 0.65 mumole/ml in vitro. On the other hand, MEHP and mono-n-octyl phthalate (MOP), a metabolite of DOP, inhibited the state 3 oxygen consumption down to a concentration of 0.065 mumole/ml. Testicular mitochondrial respiratory functions of rats administered 2 g/kg DEHP were lower than those of control or DOP-treated rats. These differences were verified by characteristics of pharmacokinetic parameters and testicular concentrations of MEHP and MOP. It may be suggested that a possible mechanism of testicular atrophy induced by DEHP may be due to direct inhibition by MEHP (and partially DEHP) of the respiratory functions of Sertoli cell mitochondria in rat testis.

Animals↗

PubMed1997

Non-invasive quantitative 31P MRS assay of mitochondrial function in skeletal muscle in situ.

A method for non-invasive, quantitative 31P NMR spectroscopic investigation of mitochondrial function in human skeletal muscle in situ is described. High time resolution 31P NMR measurements of phosphocreatine, inorganic phosphate and ATP resonances were conducted on human forearm flexor muscle during involuntary twitch contraction at eight different frequencies. Mitochondrial and glyco(geno)lytic ATP synthesis fluxes, and the cytosolic free energy of ATP hydrolysis (delta GP), were calculated at incremental steady-states of energy balance. The covariation of mitochondrial ATP synthesis flux, JPMOP, and delta GP was quasi-linear over the physiological range of free energy values. Curve-fit analysis of the covariation yielded a maximal sustainable JPMOP of 0.24 +/- 0.06 mmol ATP l-1.s-1 and a midpoint potential, (delta GP)0.5, of 58.1 +/- 1.2 kJ/mole in the muscle cells.

Adult↗

PubMed1990

Hepatic mitochondrial function and lysosomal enzyme activity in ethanol-potentiated aflatoxin B1 hepatotoxicity.

The possible role of hepatic mitochondrial function and lysosomal enzyme activity in ethanol-enhanced aflatoxin B1 (AFB1) hepatotoxicity was studied in male rats. Hepatic ATP content was significantly decreased in rats treated with ethanol (4.0 g/kg body wt.) and AFB1 (2.0 mg/kg body wt.) compared with rats treated with AFB1 alone at 12-72 h after AFB1 administration. The decrease in hepatic ATP content was due to the decrease in the activity of NADH-cytochrome c reductase whereas cytochrome oxidase activity did not differ in rats treated with ethanol and AFB1 when compared to AFB1 alone. Total and free activities of hepatic lysosomal enzymes (glucuronidase, arylsulfatase and acid phosphatase) were significantly increased in rats treated with ethanol and AFB1 at 24-36 h after AFB1 administration when compared to AFB1 alone. The increase in hepatic lysosomal enzyme activities correlated well with the increase in the lipid peroxide level of lysosomes in rats treated with ethanol and AFB1. These findings indicate that the decrease in hepatic mitochondrial respiratory enzyme activities and the increase in lipid peroxide level of lysosomes might lead to a decrease in hepatic ATP content, and that the increase in the activities of hepatic lysosomal enzymes, respectively, enhance the AFB1 hepatotoxicity of ethanol.

Acid Phosphatase↗

PubMed2006

Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells.

Previously, we showed that oxidant exposure in renal proximal tubular cells (RPTC) induces mitochondrial dysfunction mediated by PKC-epsilon. This study examined the role of ERK1/2 in mitochondrial dysfunction induced by oxidant injury and whether PKC-epsilon mediates its effects on mitochondrial function through the Raf-MEK1/2-ERK1/2 pathway. Sublethal injury produced by tert-butylhydroperoxide (TBHP) resulted in three- to fivefold increase in phosphorylation of ERK1/2 and p38 but not JNK. This was followed by decreases in basal and uncoupled respirations (41%), state 3 respiration and ATP production coupled to complex I (46%), and complex I activity (42%). Oxidant exposure decreased aconitase activity 30% but not pyruvate, alpha-ketoglutarate, and malate dehydrogenase activities. Inhibition of ERK1/2 restored basal and state 3 respirations, DeltaPsi(m), ATP production, and complex I activity but not aconitase activity. In contrast, activation of ERK1/2 by expression of constitutively active MEK1 suppressed basal, uncoupled, and state 3 respirations in noninjured RPTC to the levels observed in TBHP-injured RPTC. MEK1/2 inhibition did not change Akt or p38 phosphorylation, demonstrating that the protective effect of MEK1/2 inhibitor was not due to activation of Akt or inhibition of p38 pathway. Inhibition of PKC-epsilon did not block TBHP-induced ERK1/2 phosphorylation in whole RPTC or in mitochondria. We conclude that 1) oxidant-induced activation of ERK1/2 but not p38 or JNK reduces mitochondrial respiration and ATP production by decreasing complex I activity and substrate oxidation through complex I, 2) citric acid cycle dehydrogenases are not under control of the ERK1/2 pathway in oxidant-injured RPTC, 3) the protective effects of ERK1/2 inhibition are not due to activation of Akt, and 4) ERK1/2 and PKC-epsilon mediate oxidant-induced mitochondrial dysfunction through independent pathways.

Aconitate Hydratase↗

PubMed1993

No evidence for altered muscle mitochondrial function in Parkinson's disease.

Recent reports indicate that reductions in mitochondrial respiratory chain function occur in substantia nigra, platelets, and muscle from patients with Parkinson's disease. To confirm and further characterise the presence of a generally distributed mitochondrial defect, mitochondrial metabolism was evaluated in muscle obtained from subjects with Parkinson's disease and from normal controls. Oxygen consumption rates in muscle mitochondria represented by complex I, complexes II-III, or complex IV did not differ between the two groups. Likewise, activities of rotenone sensitive NADH cytochrome c reductase, succinate cytochrome c reductase, or cytochrome oxidase in muscle mitochondria were not significantly different between Parkinsonian and control subjects. These findings fail to provide support for a generalised defect in mitochondrial function in Parkinson's disease but do not exclude an abnormality in respiratory function confined to the substantia nigra.

Adult↗