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At least 919 records · Page 51Linked to original sources
PubMed1989

The role of long-chain acyl-CoA in the damage of oxidative phosphorylation in heart mitochondria.

The aim of this investigation was to study the effect of intramitochondrial acyl-CoA on the respiration of rabbit heart mitochondria over the whole range of stationary respiratory rates between States 4 and 3. The creatine phosphokinase system was used for stabilization of extramitochondrial adenine nucleotide concentration. It was shown that acyl-CoA depressed respiration more effectively in the intermediate range of respiration between States 4 and 3. The effect of acyl-CoA was negligible near State 4 and in State 3. These data are in line with our previous results concerning the dependence of the adenine nucleotide translocator control coefficient on the rate of mitochondrial respiration. Thus, our data suggest that long-chain acyl-CoA may regulate oxidative phosphorylation in heart mitochondria in vivo.

Acyl Coenzyme A↗
PubMed1975

On the stoichiometry between uncouplers of oxidative phosphorylation and respiratory chains. The catalytic action of SF 6847 (3,5-di-tert-butyl-4-hydroxy-benzylidenemalononitrile).

Titration of State 4 rat-liver mitochondria at pH 7.2 with the uncoupler 3,5-di-tert-butyl-4-hydroxybenzylidenemalononitrile (SF 6847) at various concentrations of mitochondria and using various substrates indicates that under optimal conditions less than 0.2 molecule of 3,5-di-tert-butyl-4-hydroxybenzylidenemalononitrile per respiratory chain is sufficient to induce complete uncoupling. This result suggests that there is not a stoichiometric relationship between uncoupler molecules and cytochrome c oxidase, involved in oxidative phosphorylation, or between the former and phosphorylation assemblies. Experiments on the release by 3,5-di-tert-butyl-4-hydroxybenzylidenemalononitrile of azide-inhibited respiration of State 3 mitochondria and titrations with 5-chloro-3-tert-butyl-2'-chloro-4'-nitrosalicylanilide (S13) of State 4 mitochondria at various mitochondrial concentrations confirm this conclusion.

Aniline Compounds↗
PubMed1981

Oxidative phosphorylation and mitochondrial physiology: a critical review of chemiosmotic theory, and reinterpretation by the association-induction hypothesis.

Fundamental assumptions of the chemiosmotic hypothesis of Mitchell are examined. Comparison of these assumptions with experimental data accumulated over the past fifty years leads to the conclusion that the hypothesis has not been supported. A review of important findings concerning the physical state of the major intracellular cation potassium shows clearly that this ion does not exist in a free state but is adsorbed on specific anionic sites. These findings refute the membrane-pump theory but added powerful support for the association-induction hypothesis, on the basis of which a new mechanism of oxidative phosphorylation as well as a wide variety of mitochondrial behaviors are proposed and compared with experimental data.

Adenosine Triphosphate↗
PubMed1984

Respiratory activity and oxidative phosphorylation in mitochondria of the rat brain and liver under conditions of elevated temperature of the environment.

The rate of oxygen consumption by mitochondrial fractions of the brain and liver of rats under elevated ambient temperature was investigated. The animals were placed in a thermostatized chamber for 6 hours at 21 degrees, 28 degrees or 37 degrees C. During the experiment, relative humidity in the chamber was controlled. After exposure, the animals were decapitated, mitochondrial fractions isolated and oxygen consumption measured with the Clark electrode. Respiratory substrates of succinate and glutaminate with malate were used. The analysis of the obtained results was based on the t-Student test, assuming the values obtained for the animals staying at 21 degrees as the control values. It was found that the 6 hrs stay under the ambient hyperthermy conditions did not induce any disturbances in the respiratory processes and oxidative phosphorylation in rat's brain and liver mitochondria.

Animals↗
PubMed2002

Oxidative phosphorylation enzyme complexes in caloric restriction.

Free radicals, generated especially by electron leakage from mitochondrial electron transport chain (ETC), are accepted as one of the possible causes of aging. Long-term caloric restriction (CR) is known to increase the species specific average and maximum life spans. Thus it provides a means for investigating mechanisms of aging. There is evidence suggesting a decrease in the free radical production with CR. In this study, Blue-Native PAGE (BN-PAGE) technique was used to investigate the effect of CR on the oxidative phosphorylation enzyme complexes. Of the total 30 female Swiss Albino balb/c mice, 15 were used as control and the other 15 as CR group. Alternate day feeding regimen was used in the CR group for 66 weeks beginning at the end of 3rd month. In the control group, 5 (33.3%) mice died, 3 (20%) of them of breast cancer, 2 (13.3%) of unknown causes and no death cases were observed in the CR group during the study. BN-PAGE was performed on the extracts from brain mitochondrial fractions. Complexes II and V were excluded from the study due to some analytical limitations. No difference was found in the levels of complexes I and III between the groups. In the CR group, complex IV level was found increased and the ratio of complex III-IV decreased compared with the control group. Since there is a slight increase (108%) in the level of complex IV in the CR group, our results could suggest possible partial compensation of electron leakage in the upstream complexes in ETC, and the decrease of free radical production with CR.

Adenosine Triphosphatases↗
PubMed1985

Studies on the mechanism of oxidative phosphorylation: effects of specific F0 modifiers on ligand-induced conformation changes of F1.

Aurovertin is a fluorescent antibiotic that binds to the catalytic beta subunits of the mitochondrial F1-ATPase and inhibits ATP synthesis and hydrolysis. ATP, ADP, and membrane energization in submitochondrial particles (SMP) alter the fluorescence of F1-bound aurovertin. These fluorescence changes are considered to be in response to the conformation changes of F1-ATPase. This paper shows that the ATP-induced fluorescence change of aurovertin bound to SMP or complex V (purified ATP synthase complex F0-F1) is inhibited when these preparations are pretreated with oligomycin or N,N'-dicyclohexylcarbodiimide (DCCD). This inhibition is not seen with isolated F1-ATPase. These and other results have suggested that modifications of the DCCD-binding protein in the membrane sector (F0) of the ATP synthase complex are communicated to F1, thereby altering the binding characteristics of ATP to the beta subunits. By analogy, it is proposed that modifications (e.g., protonation/deprotonation) of the DCCD-binding protein effected by protonic energy alter the conformation of F1 and bring about the substrate/product binding changes that appear to be essential features of the mechanism and regulation of oxidative phosphorylation.

Adenosine Triphosphate↗
PubMedDate not supplied

[Acidosis inhibits oxidative phosphorylation in intrasynaptosomal mitochondria by releasing calcium from cytoplasmic store].

The origin of calcium responsible for earlier observed acidosis-induced decrease in ATP content and inhibition of respiration in rat brain synaptosomes was studied. Acidosis (pH 6.0) inhibits both basal and potassium-stimulated 45Ca2+ uptake (60 mM KCl). Calcium channel blockers verapamil (100 microM) and 45Ca2+ (100 microM) have no effect on the level of ATP and respiration rate at pH 6.0. Theophylline (10 mM) releasing calcium from intracellular stores lowered ATP and O2 consumption rate at pH 7.4 but not at pH 6.0 being effective only in calcium-containing medium. Inhibitor of calcium transport in mitochondria ruthenium red (10 microM) prevented acidosis-induced ATP decrease. It is suggested that acidosis inhibits oxidative phosphorylation by releasing calcium from cytoplasmic stores with its subsequent transport into intrasynaptosomal mitochondria.

Acidosis↗
PubMedDate not supplied

A simple universal mechanism of use and conservation of energy: its application to movements of ions and other materials across cell, mitochondrial and other membranes and to oxidative phosphorylation.

A single simple mechanism by which all cells might both use energy to drive active transport to all solutes and also conserve energy in the form of adenosinetriphosphate (ATP) is descirbed. The basic assumption is that injection of energy results in a conformational change of the membrane which both generates transient highly-ordered water structures on its inside surface and changes membrane permeability. Ordered water is propagated through the cell by means of cooperative interactions with proteins, so that during the ordered period intracellular water is incompatible with small cations which require strong primary hydration, but has enhanced affinity for water-structure-breaking solutes. In animal cells cytoplasmic water is ordered by the activity of the plasma-membrane-bound transport ATPases. In mitochondria and bacteria the state of ordered water is identified with the energised state, which can be generated either by passage of electrons down the electron chain, or by ATPase activity. The mechanism is shown to be consistent with the observed transport activities of mitochondria and bacteria, and also provides a simple direct explanation of oxidative phosphorylation.

Adenosine Triphosphate↗
PubMed2001

Differential effects of nucleoside analogs on oxidative phosphorylation in human pancreatic cells.

Although nucleoside analogs as a group inhibit mtDNA replication, individually they target specific organs for toxicity. For example, dideoxyinosine (ddI) is most closely associated with clinical pancreatitis and dideoxycytosine (ddC) with peripheral neuropathy. Comparison of the differential effects of these analogs on mitochondrial function in relevant human cell lines could provide general clues as to the mechanisms of their differential toxicity. We compared the effects of ddI [and its intracellular metabolite dideoxyadenosine (ddA)], with other nucleoside analogs ddC, Azidothymidine (AZT) and didehydrodeoxythymidine (d4T) on mtDNA elongation, cytotoxicity, oxidative phosphorylation, and cellular ATP concentration in a human pancreatic cell line, Capan-1 cells. AZT, like all the other analogs tested, altered mtDNA elongation, but had no other effect on these cells. Both ddC and d4T, but not ddI (20 microm and 50 microM), reduced total dish protein (a measure of cell numbers) in cells grown to confluence. The effect of ddA was intermediate. All (except AZT) increased lactate concentration in the cell culture medium. Dideoxycytosine (ddC) and d4T did not significantly affect cell oxygen consumption, expressed as a fraction of total dish protein. By contrast, ddI and ddA reduced basal and/or FCCP-stimulated oxygen consumption. Dideoxycytosine (ddC) but not ddI or ddA (50 microM) was cytotoxic to cells after six days of growth. Nevertheless, the ATP content (expressed as a fraction of surviving cells) for ddC-, ddI-, and ddA-treated cells was similar to control cells. Cytotoxicity was apparent for ddI, ddA, as well as ddC after seven days. Paradoxically, cell ATP content was now significantly higher than control cells. Electron microscopy of cells treated with ddI confirmed significant ultrastructural changes affecting the inner mitochondria membrane and cristae. In conclusion, these data suggest that nucleoside analogs uniformly induce damage to mtDNA. However, the mitochondrial phenotypic damage induced by ddI and ddA appear to result in less Capan-1 cytotoxicity than ddC and d4T. The link between these differential effects and ddI pancreatitis is unclear.

Antimetabolites↗
PubMed2003

Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats.

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, alpha-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.

Aconitate Hydratase↗
PubMedDate not supplied

Focal deficiency of cytochrome c oxidase and of mitochondrial ATPase with histochemical evidence of loosely coupled oxidative phosphorylation in a mitochondrial myopathy of a patient with bilateral ptosis. An enzyme histochemical, immunocytochemical and fine structural study.

In the skeletal muscle of a patient with bilateral ptosis suggestive of progressive external ophthalmoplegia (PEO), but without ragged red fibres, electron microscopy revealed a moderate proliferation of mitochondria in nearly all fibres. A focal absence of cytochrome c oxidase and of mitochondrial ATPase was demonstrated histochemically in 3.2% and 1.4% respectively of the fibres. In 0.9% of the fibres both enzymes were deficient. In addition, mitochondrial ATPase, the ATP-synthesizing enzyme latent in controls, showed activation already before addition of an uncoupler. This indicates loosely coupled oxidative phosphorylation. The findings point to a complex derangement of mitochondrial function. Immunocytochemistry of cytochrome c oxidase favours the assumption that the defect is based on a highly diminished content of immunoreactive enzyme protein.

Adenosine Triphosphatases↗
PubMed2000

Frataxin activates mitochondrial energy conversion and oxidative phosphorylation.

Friedreich's ataxia (FA) is an autosomal recessive disease caused by decreased expression of the mitochondrial protein frataxin. The biological function of frataxin is unclear. The homologue of frataxin in yeast, YFH1, is required for cellular respiration and was suggested to regulate mitochondrial iron homeostasis. Patients suffering from FA exhibit decreased ATP production in skeletal muscle. We now demonstrate that overexpression of frataxin in mammalian cells causes a Ca(2+)-induced up-regulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential (delta psi(m)) and results in an elevated cellular ATP content. Thus, frataxin appears to be a key activator of mitochondrial energy conversion and oxidative phosphorylation.

3T3 Cells↗
PubMed2001

Na+ effects on mitochondrial respiration and oxidative phosphorylation in diabetic hearts.

Intracellular Na+ is approximately two times higher in diabetic cardiomyocytes than in control. We hypothesized that the increase in Na+i activates the mitochondrial membrane Na+/Ca2+ exchanger, which leads to loss of intramitochondrial Ca2+, with a subsequent alteration (generally depression) in bioenergetic function. To further evaluate this hypothesis, mitochondria were isolated from hearts of control and streptozotocin-induced (4 weeks) diabetic rats. Respiratory function and ATP synthesis were studied using routine polarography and 31P-NMR methods, respectively. While addition of Na+ (1-10 mM) decreased State 3 respiration and rate of oxidative phosphorylation in both diabetic and control mitochondria, the decreases were significantly greater for diabetic than for control. The Na+ effect was reversed by providing different levels of extramitochondrial Ca2+ (larger Ca2+ levels were needed to reverse the Na+ depressant effect in diabetes mellitus than in control) and by inhibiting the Na+/Ca2+ exchanger function with diltiazem (a specific blocker of Na+/Ca2+ exchange that prevents Ca2+ from leaving the mitochondrial matrix). On the other hand, the Na+ depressant effect was enhanced by Ruthenium Red (RR, a blocker of mitochondrial Ca2+ uptake, which decreases intramitochondrial Ca2+). The RR effect on Na+ depression of mitochondrial bioenergetic function was larger in diabetic than control. These findings suggest that intramitochondrial Ca2+ levels could be lower in diabetic than control and that the Na+ depressant effect has some relation to lowered intramitochondrial Ca2+. Conjoint experiments with 31P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na+ (3-30 mM) led to significantly decreased ATP levels in diabetic rats, but produced smaller changes in control. These data support our hypothesis that in diabetic cardiomyocytes, increased Na+ leads to abnormalities of oxidative processes and subsequent decrease in ATP levels, and that these changes are related to Na+ induced depletion of intramitochondrial Ca2+.

Adenosine Triphosphate↗
PubMed1991

Mechanistic stoichiometry of mitochondrial oxidative phosphorylation.

P/O ratios of rat liver mitochondria were measured with particular attention to systematic errors. Corrections for energy loss during oxidative phosphorylation were made by measurement of respiration as a function of mitochondrial membrane potential. The corrected values were close to 1, 0.5, and 1 at the three coupling sites, respectively. These values are consistent with recent measurements of mitochondrial proton transport.

Adenosine Diphosphate↗
PubMed1993

In situ autolysis of mouse brain: ultrastructure of mitochondria and the function of oxidative phosphorylation and mitochondrial DNA.

The effect of in situ autolysis on cerebral mitochondrial structure and function has been investigated. Mice (n = 9) were sacrificed and stored for up to 24 h under unfavorable post-mortem conditions at 25 degrees C. At different time intervals groups of three animals were submitted to post-mortem dissection and tissue from different regions of the brain was used for the preparation of "free" and synaptosomal mitochondria. On electron microscopic examination, the post-mortem period had no significant influence on mitochondrial morphology and enzymatic activities of complexes I-V of the mitochondrial oxidative phosphorylation system were still present in all the mitochondrial preparations from different regions of the brain, albeit at a reduced levels. Degradation of mitochondrial DNA was virtually absent from mitochondrial preparations during the 24-h period of autolysis, as shown by the presence of intact DNA by Southern blot and PCR analysis. Based on these results, alterations in mitochondrial DNA and deficiencies of mitochondrial respiratory complexes I-V can be recognized in cerebral tissue even after 24 h of unfavorable post-mortem storage conditions.

Animals↗
PubMed1982

The role of the adenine nucleotide translocator in oxidative phosphorylation. A theoretical investigation on the basis of a comprehensive rate law of the translocator.

A minimum model of adenine nucleotide exchange through the inner membrane of mitochondria is presented. The model is based on a sequential mechanism, which presumes ternary complexes formed by binding of metabolites from both sides of the membrane. The model explains the asymmetric kinetics of ADP-ATP exchange as a consequence of its electrogenic character. In energized mitochondria, a part of the membrane potential suppresses the binding of extramitochondrial ATP in competition with ADP. The remaining part of the potential difference inhibits the back exchange of internal ADP for external ATP. The assumption of particular energy-dependent conformational states of the translocator is not necessary. The model is not only compatible with the kinetic properties reported in the literature about the adenine nucleotide exchange, but it also correctly describes the response of mitochondrial respiration to the extramitochondrial ATP/ADP ratio under different conditions. The model computations reveal that the translocation step requires some loss of free energy as driving force. The size of the driving force depends depends on the flux rate as well as on the extra- and intramitochondrial ATP/ADP quotients. By both quotients the translocator control the export of ATP formed by oxidative phosphorylation in mitochondria.

Adenosine Diphosphate↗
PubMed1994

[Stimulation of respiration in liver mitochondria by glucose in the absence of hexokinase activity. The effect of saccharose and several inhibitors of oxidative phosphorylation].

The effect of glucose on rat liver mitochondrial respiration after elimination of possible phosphorylation by mitochondrial hexokinase has been studied. It has been found that during isolation of mitochondria without washing and their subsequent washing with KCl-media glucose stimulates state 3 respiration but has no effect on the rate of state 4 respiration or on the uncoupler (2.4-dinitrophenol)-mediated respiration. The half-maximum effect is observed at the glucose concentration of about 2.4 mM. Washing of mitochondria with KCl or their isolation in a sucrose-containing medium without washing eliminates the stimulating effect of glucose. The sucrose present in the incubation medium suppresses the stimulating effect of glucose in a competitive manner. Oligomycin removes the stimulating effect when used at concentrations causing the suppression of state 3 mitochondrial respiration by 20%. Under these conditions carboxyatracytyloside markedly enhances the glucose effect. It is concluded that glucose controls the oxidative phosphorylation, acting as an adenine nucleotide translocator.

2,4-Dinitrophenol↗
PubMed1983

The mechanism of inhibition of mitochondrial oxidative phosphorylation by the nonsteroidal anti-inflammatory agent diflunisal.

The anti-inflammatory agent diflunisal was found to induce a progressive loss of respiratory control in tightly coupled rat liver mitochondria, starting at low concentrations (3.3 microM). This loss of control was accompanied by a stimulation of state 4 respiration in the presence of either succinate or glutamate plus malate as the respiratory substrate. The inhibition of state 3 respiration by oligomycin was released by diflunisal. Mitochondrial ATP hydrolysis was stimulated by diflunisal over the same concentration range that affected state 4 respiration: the stimulation was inhibited by oligomycin. It was concluded that diflunisal was acting as an uncoupler of mitochondrial oxidative phosphorylation. An identical action was found in mitochondria isolated from the livers of mice, rabbits and guinea-pigs. Potencies similar to diflunisal were found with flufenamic acid and mefenamic acid, but other anti-inflammatory agents were either less potent or inactive.

Adenosine Triphosphatases↗