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PubMed1981

[Tissue-specific regulation of rat liver mitochondrial oxidative phosphorylation by a soluble phase of cells from that organ].

Tissue specificity of mitochondrial respiration stimulation under the effect of a soluble phase of liver cells (SPC) is preserved by addition to dinitrophenol but is reserved in the presence of oligomycin. Addition of rotenon in the presence of SPC entails a tissue-specific increase in respiration that is proportional to the respective increase in respiration of intact mitochondria in the presence of the inhibitor mentioned. SPC tissue-specifically inhibits ATPase activity of liver mitochondria. This fraction of SPC is capable of recovering the coupling of oxidative phosphorylation of mitochondria whose respiration is inhibited by adding ADP. A conclusion is made that SPC is capable not only to decrease tissue-specifically the coupling of intact mitochondria but also to raise it in mitochondria with deranged oxidative phosphorylation. This assures intratissue organization of liver metabolism by means of tissue-specific stabilization of liver cell energy metabolism.

2,4-Dinitrophenol↗
PubMed1991

An extended dynamic model of oxidative phosphorylation.

The presented model based on an earlier one (Korzeniewski, B. and Froncisz, W. (1989) Studia Biophys. 132, 173-187) simulates concentration changes in time of chemical compounds and thermodynamic forces during respiration of cell suspension in a closed chamber. A set of differential equations solved numerically describes the utilization of oxygen up to anaerobiosis and the behaviour of the system after a sudden pulse of oxygen. Flux control coefficients for most important reactions (enzymes) of oxidative phosphorylation were calculated. A good qualitative and (when a direct comparison is possible) quantitative agreement with experimental results can be observed. The following conclusions can be drawn from the simulation: (1) Wilson's steady state model is not in contradiction with sharing of the control over the respiration between some steps and displacement of the ATP/ADP carrier from equilibrium. (2) The overshoot characteristics of the delta microH+ time-course after reoxygenation can be explained without using the lag-phase kinetics of ATP-synthetase. (3) A 'hot region' (sharp changes of many parameters) can be distinguished when the oxygen concentration approaches zero; only cytochrome oxidase is clearly sensitive on oxygen concentration in all its range. (4) Control over oxidative phosphorylation is shared mainly between inputs of the system (ATP utilization and substrate dehydrogenation) and the proton leak.

Adenine Nucleotides↗
PubMed2006

Up-regulation of genes for oxidative phosphorylation and protein turnover in diabetic mouse retina.

Diabetic retinopathy is one of the most frequent complications of diabetes and is a leading cause of vision loss in adulthood. To better understand the molecular pathophysiology of diabetic retinopathy, we performed comprehensive gene expression analysis of the mouse retina under diabetic conditions with an in-house cDNA microarray system that was designed to be suitable for the small amount of RNA available from a single mouse retina. Diabetes was induced in male C57BL/6 mice by an intraperitoneal injection of streptozotocin, and the changes in retinal mRNA levels were examined in three pairs of diabetic and age-matched control mice at 1 and 3 months after the injection of streptozotocin. Northern blot analysis with amplified total cRNA confirmed the increase in mRNA levels of several selected genes. Most of the significantly up-regulated genes could be classified into two functional categories: oxidative phosphorylation and protein turnover. All mitochondrial DNA-encoded and most of the nuclear DNA-encoded genes for oxidative phosphorylation were up-regulated in the diabetic retina. This was in sharp contrast with a previous report of a down-regulation of these genes in skeletal muscles of streptozotocin-induced diabetic mice and type 2 diabetic humans. Genes for protein synthesis and ubiquitin were also up-regulated in the diabetic retina, suggesting the increase in turnover rates for at least a part of the protein population. Taken together, the diabetic retina appears to be in a state activated for intermediary metabolism, presumably because of an increase in insulin-independent glucose influx. These results provide insights into possible preventive and therapeutic intervention of diabetic retinopathy.

Animals↗
PubMed1976

[Oxidative phosphorylation in the myocardium of patients with mitral valve stenosis during surgery].

In 135 patients with mitral stenosis of the III and IV stages oxidative phosphorylation in the mitochondria of the left cardiac auricle was studied by the polarographic method. A uniform lowering of the mitochondrial respiration at different metabolic states with IV stage of the affection and in patiens of a more advanced age (36-52 years) was demonstrable. In some instances the conjugation of oxidation and phosphorylation was on a decline too. A nitrous oxide anesthesia (by comparison with the ether-oxygen one) produced a substantial depression of the mitochondrial respiration, especially when alpha-ketoglutarate was used. The sensitivity to the inhibitory effect of nitrous oxide in the elderly was higher. Respiration with succinate as a substrate in the young (20-35 years) patients proved little sensitive to the suppressing action of this type of anesthesia.

Adult↗
PubMed1973

Reconstitution of oxidative phosphorylation and the adenosine triphosphate-dependent transhydrogenase activity by a combination of membrane fractions from unCA- and uncB- mutant strains of Escherichia coli K12.

1. Membrane preparations from both uncA(-) and uncB(-) mutant strains of Escherichia coli K12, in which electron transport is uncoupled from phosphorylation, were fractionated by washing with a low-ionic-strength buffer. The fractionation gave a ;5mm-Tris wash' and a ;membrane residue' from each strain. This technique, applied to membranes from normal cells, separates the Mg(2+),Ca(2+)-stimulated adenosine triphosphatase activity from the membrane-bound electron-transport chain and the non-energy-linked transhydrogenase activity. 2. Reconstitution of both oxidative phosphorylation and the ATP-dependent transhydrogenase activity was obtained by a combination of the ;membrane residue' from strain AN249 (uncA(-)) with the ;5mm-Tris wash' from strain AN283 (uncB(-)). 3. Valinomycin plus NH(4) (+) inhibited oxidative phosphorylation both in membranes from a normal strain of E. coli and in the reconstituted membrane system derived from the mutant strains. 4. The electron-transport-dependent transhydrogenase activity was located in the membrane residue and was de-repressed in both the mutant strains. 5. The spatial and functional relationships between the proteins specified by the uncA and uncB genes and the transhydrogenase protein are discussed.

Adenosine Triphosphatases↗
PubMed2005

Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation.

Mammalian cells detect decreases in oxygen concentrations to activate a variety of responses that help cells adapt to low oxygen levels (hypoxia). One such response is stabilization of the protein HIF-1 alpha, a component of the transcription factor HIF-1. Here we show that a small interfering RNA (siRNA) against the Rieske iron-sulfur protein of mitochondrial complex III prevents the hypoxic stabilization of HIF-1 alpha protein. Fibroblasts from a patient with Leigh's syndrome, which display residual levels of electron transport activity and are incompetent in oxidative phosphorylation, stabilize HIF-1 alpha during hypoxia. The expression of glutathione peroxidase or catalase, but not superoxide dismutase 1 or 2, prevents the hypoxic stabilization of HIF-1 alpha. These findings provide genetic evidence that oxygen sensing is dependent on mitochondrial-generated reactive oxygen species (ROS) but independent of oxidative phosphorylation.

Electron Transport Complex III↗
PubMed2006

Oxidative phosphorylation and aging.

This review addresses the data that support the presence and contribution of decreased mitochondrial oxidative phosphorylation during aging to impaired cellular metabolism. Aging impairs substrate oxidation, decreases cellular energy production and increases the production of reactive intermediates that are toxic to the cell. First, the basic principles of mitochondrial oxidative physiology are briefly reviewed. Second, the focus on the relationship of altered mitochondrial respiration to the increased production of reactive oxygen species that are employed by the "rate of living" and the "uncoupling to survive" theories of aging are discussed. Third, the impairment of function of respiration in aging is reviewed using an organ-based approach in mammalian systems. Fourth, the current state of knowledge regarding aging-induced alterations in the composition and function of key mitochondrial constituents is addressed. Model organisms, including C. elegans and D. melanogaster are included where pertinent. Fifth, these defects are related to knowledge regarding the production of reactive oxygen species from specific sites of the electron transport chain.

Aging↗
PubMed1995

Analysis of oxidative phosphorylation complexes in cultured human fibroblasts and amniocytes by blue-native-electrophoresis using mitoplasts isolated with the help of digitonin.

The electrophoretic method of Schägger and von Jagow (Anal. Biochem. 199, 233-231 (1991) was adapted to allow analysis of enzymes of the respiratory chain and the ATP-synthase in cultured human skin fibroblasts and amniocytes. The cells were fractionated with digitonin and mitoplasts were isolated and used for electrophoresis. The purification of mitoplasts and the resolution by electrophoresis of the oxidative phosphorylation complexes were optimal when 0.8-1.6 mg of digitonin/mg protein was used. Intact complexes I, III, IV, and V were clearly separated by blue native-polyacrylamide gel electrophoresis (PAGE) in the first dimension and their individual subunits by tricine-sodium dodecyl sulfate-PAGE in the second dimension. Approximately 10(6) fibroblasts or amniocytes (0.4-0.6 mg protein) were sufficient for complete analysis of the oxidative phosphorylation complexes using detection by staining and by Western blotting. Comparable resolution was obtained with other cell types. Studies of fibroblasts from patients with cytochrome c oxidase deficiency demonstrated the usefulness of the method for diagnosis of mitochondrial disorders.

Amniotic Fluid↗
PubMedDate not supplied

Activation of mitochondrial oxidative phosphorylation during (+/-)-isoproterenol-induced cell injury of myocardium.

Hydrolytic and synthetic activities of mitochondrial ATPase were studied during (+/-)-isoproterenol-induced cell injury of the myocardium (67 mg/kg body weight). This research was a long-term study (72 h) in which rat heart homogenates, and a potentiometric method were used. Hydrolytic activities in homogenates from (+/-)-isoproterenol-treated rats were not statistically different, during the whole long-term study, from the hydrolytic activity in normal homogenates. The synthetic activity (mitochondrial oxidative phosphorylation) of mitochondrial ATPase increased at 3, 6, and 18 h (35, 48 and 23% respectively) after (+/-)-isoproterenol administration with regard to the control group. At 12 h and 21-72 h after drug administration, the data revealed no differences between synthetic activity of mitochondrial ATPase in control vs (+/-)-isoproterenol treated homogenates. The facts that synthetic and hydrolytic activities in homogenates from (+/-)-isoproterenol treated rats were never lower than the synthetic and hydrolytic activities in normal homogenates, and that activation of mitochondrial oxidative phosphorylation occurred at some times after (+/-)-isoproterenol treatment, suggest that no considerable and "negative" modifications occur in the active configuration of mitochondrial ATPase during (+/-)-isoproterenol-induced injury of the myocardium (67 mg/kg body weight).

Adrenergic beta-Agonists↗
PubMed1975

The disturbance of oxidative phosphorylation by N-acetoxy-N-acetyl-2-aminofluorene, a model ultimate carcinogen.

Currently N-acetoxy-N-acetyl-2-aminofluorene is favored by many investigators to be a model of the ultimate electrophilic carcinogenic agent derived metabolically from the carcinogen N-acetyl-2-aminofluprene. The model induced in vitro a delayed ATP energized increase in mitochondrial volume as indicated by the decrease in absorbancy at 520 nm. The ATP energized decrease in absorbancy was inhibited by rutamycin, 2,4-dinitrophenol and a high level of antimycin known to induce ATPase activity. The known to inhibit respiration without inducing ATPase activity. Malate or potassium ion did not affect the phenomenon, however, sulfate ion which has been implicated in liver carcinogenesis shortened the induction period. Showdomycin stimulated the phenomenon. N-Acetoxy-N-acetyl-2-aminofluorene interacts with the machinery of oxidative phosphorylation. N-Acetoxy-N-acetyl-2-aminofluorene was enzymically converted by the mitochondria to N-hydroxy-N-acetyl-2-aminofluorene. These findings extend the experimental confluence of oxidative phosphorylation with carcinogenesis.

Acetoxyacetylaminofluorene↗
PubMed1985

Effect of ochratoxin A on rat liver mitochondrial respiration and oxidative phosphorylation.

The in vitro effects of ochratoxin A on the membrane structure and bioenergetic functions of rat liver mitochondria were studied. It was found that when the toxin was added to the assay medium the respiratory control of the isolated mitochondria was decreased as the concentration of the toxin increased. The mitochondrial respiration was gradually uncoupled by the toxin when its concentration was raised above 1.2 X 10(-6) M, and became fully uncoupled at 6.2 X 10(-4) M. The oxidative phosphorylation was not damaged until the toxin concentration was higher than 9.3 X 10(-5) M. On the other hand, ochratoxin A inhibited the electron transfer functions of the mitochondria. At the concentration above 1.0 X 10(-4) M, ochratoxin A inhibited the succinate dehydrogenase, succinate-cytochrome c reductase, and succinate oxidase activities of the respiratory chain. Fifty percent of succinate-cytochrome c reductase and succinate oxidase activity was lost in the presence of 8.0 X 10(-4) and 6.2 X 10(-4) M ochratoxin A, respectively. The inhibition kinetic studies revealed that ochratoxin A is an uncompetitive inhibitor of both succinate-cytochrome c reductase and succinate dehydrogenase, and the inhibition constants for the 2 enzyme activities were estimated to be 4.4 X 10(-4) and 2.2 X 10(-4) M, respectively. However, the toxin did not inhibit either cytochrome oxidase or NADH dehydrogenase activity of the mitochondrial respiratory chain. It is thus concluded that ochratoxin A exerts its effect on the mitochondrial respiration and oxidative phosphorylation through the impairment of the mitochondrial membrane and inhibition of the succinate-supported electron transfer activities of the respiratory chain.

Adenosine Diphosphate↗
PubMed2001

Effect of insulin on oxygen free radicals and oxidative phosphorylation in liver mitochondria of diabetic rats.

AIM: To observe the effects of insulin on liver mitochondrial respiratory function, activity of H+-ATPase, and superoxide anion free radicals production in diabetic rats. METHODS: Rats were injected iv with alloxan 40 mg/kg to induce diabetes. The liver mitochondrial respiratory function was assayed by measurement of oxygen consumption using a Clark oxygen electrode. Superoxide anion production was assayed using chemiluminescence method. Activities of H+-ATPase were measured by luciferin-luciferase system and inorganic phosphorus's method. RESULTS: Insulin 1 U/kg sc daily for 9 weeks improved oxidative phosphorylation, respiratory rate state 3 (P < 0.05), respiratory control ration (P < 0.01), and ADP:O ratio (P < 0.01), but there were no obvious effect on respiratory rate state 4 (P > 0.05). In the insulin group, synthesis activity of H+-ATPase was obviously increased (P < 0.05) and hydrolytic activity of H+-ATPase was remarkably decreased (P < 0.01), compared with the diabetes group. Insulin 1 U/kg for 9 weeks apparently decreased the production of O2.- (P < 0.01) in liver mitochondria of diabetic rats. CONCLUSION: Insulin can prevent the injury from superoxide anion in liver mitochondria, and improve the function of the liver mitochondria oxidative phosphorylation.

Adenosine Triphosphatases↗
PubMed2006

Uncoupling of oxidative phosphorylation enables Candida albicans to resist killing by phagocytes and persist in tissue.

After five serial passages of Candida albicans SC5314 through murine spleens by intravenous inoculation, we recovered a respiratory mutant (strain P5) that exhibited reduced colony size, stunted growth in glucose-deficient media, increased oxygen consumption and defective carbohydrate assimilation. Strain P5 was indistinguishable from SC5314 by DNA typing methods, but had a greater concentration of mitochondria by SYTO18 staining. Treatment with various inhibitors demonstrated that strain P5's electron transport chain was intact and oxidative phosphorylation was uncoupled. During disseminated candidiasis, the mutant did not kill mice or cause extensive damage to kidneys. The burden of strain P5 within kidneys on the first 3 days of disseminated candidiasis was significantly reduced. By days 28 and 60, it was similar to that at the time of death among mice infected with SC5314, suggesting that the mutant persisted and proliferated without killing mice. Strain P5 was resistant to phagocytosis by neutrophils and macrophages. It was also significantly more resistant to paraquat, suggesting that it is able to neutralize reactive oxygen species. Our findings indicate that regulation of respiration influences the interaction between C. albicans and the host. Uncoupling of oxidative phosphorylation might be a mechanism by which the organism adapts to stressful host environments.

Animals↗
PubMed2006

Diabetic nephropathy is associated with gene expression levels of oxidative phosphorylation and related pathways.

The in vitro behavior of skin fibroblasts from patients with or without diabetic nephropathy is associated with diabetic nephropathy risk. Here we compared skin fibroblast gene expression profiles from two groups of type 1 diabetic patients: 20 with very fast ("fast-track") versus 20 with very slow ("slow-track") rates of development of diabetic nephropathy lesions. Gene expression profiles of skin fibroblasts grown in 25 mmol/l glucose for 36 h were assessed by Affymetrix HG-U133A GeneChips to determine the proportion of genes in a given biological pathway that were directionally consistent in their group differences. Five pathways reached statistical significance. All had significantly greater proportions of genes with higher expression levels in the fast-track group. These pathways, the first four of which are closely related and have overlapping genes, included oxidative phosphorylation (P<0.001), electron transport system complex III (P=0.017), citrate cycle (P=0.037), propanoate metabolism (P=0.044), and transcription factors (P=0.046). These results support the concept that oxidative phosphorylation and related upstream pathways may be important in the pathogenesis of diabetic nephropathy. Whether these findings reflect inherent genetic cellular characteristics, "cell memory," or both requires further study.

Adult↗
PubMed1989

[Modulation of the inhibiting effect of long-chained acyl-CoA on oxidative phosphorylation of liver mitochondria in rats of various lines by Z-protein].

The effect of short-term starvation on the energy state of the adenine nucleotide system in the livers of rats of Wistar and Wag strains was studied. In fed rats, (4 hours after food withdrawal) both strains had the same liver content of long-chain acyl-CoAs. At the same time, in the livers of Wistar rats the phosphate potential values were much higher than in the livers of Wag rats (1.82 +/- 0.18 and 0.64 +/- 0.08, respectively), thus suggesting a strong inhibition of oxidative phosphorylation in the livers of Wag rats. Based on a comparison of the states and levels of Z-protein in the livers of fed and starved Wistar and Wag rats, it was proposed that an excess of long-chain acyl-CoAs over the Z-protein content in the liver is a necessary prerequisite for the development of inhibition of oxidative phosphorylation. Thus, the Z-protein may be considered as a possible physiological modulator of the inhibitory effect of acyl-CoAs on the energy state of the adenine nucleotide system in the liver in vivo.

Acyl Coenzyme A↗
PubMed1987

Defects in oxidative phosphorylation. Biochemical investigations in skeletal muscle and expression of the lesion in other cells.

Mitochondria are very vulnerable to genetic and environmental damage. If a patient is suspected of having a mitochondrial disease, elevated blood lactate, lowered blood free carnitine, abnormal urinary organic acids and carnitine esters and tissue histopathology may help with the diagnosis. For biochemical assessment of the defect, muscle is the tissue of choice even when involvement of other organs like heart or brain is more prominent. We have studied isolated muscle mitochondria and homogenates from muscle biopsies in 250 patients, and have detected in more than one third mitochondrial defects in oxidative phosphorylation, dehydrogenases, non-redox enzymes catalyzing synthesis of fuel molecules and in the carnitine system. Several patients showed more than one defect. We have selected eight patients to illustrate how a relatively simple series of investigations in both isolated mitochondria and homogenate can be used for the identification of defects in oxidative phosphorylation in a small amount of muscle (200 mg or more). Identification of the defect(s) is important since it may provide the basis for rational treatment. A minority of the patients recovered partly or completely, which is unique in treatment of inborn errors of subcellular organelles. An important aspect of mitochondrial dysfunction is the tissue specificity. The defect may be systemic but is often clinically expressed in only one or a few tissues. Rarely, tissue-specific defects can be understood on the basis of tissue-specificity of mitochondrial (iso-)enzymes. Mitochondrial deficiencies of all biotin enzymes and most CoA-linked enzymes are expressed in fibroblasts; most respiratory chain defects are not. When mitochondrial ATP synthesis has been compromised by a mitochondrial defect, secondary lesions may be generated by changes in mitochondrial protein synthesis, activated proteases and phospholipases, increased matrix CoA and resulting carnitine deficiency, decrease in Krebs cycle intermediates and increased free radical formation and lipid peroxidation.

Adolescent↗
PubMed1968

Molar growth yields as evidence for oxidative phosphorylation in Streptococcus faecalis strain 10Cl.

During the aerobic growth of Streptococcus faecalis strain 10C1, with limiting levels of glucose as the substrate, a molar growth yield (Y) of 58.2 g (dry weight) per mole of glucose was obtained. Under these conditions of growth, glucose was dissimilated primarily to acetate and CO(2). The incorporation of (14)C-glucose into cell material was no greater under aerobic conditions than during anaerobic growth. Assuming an adenosine triphosphate coefficient of 10.5, the aerobic Y cannot be explained solely on the basis of substrate phosphorylation and would appear to substantiate previous enzymatic evidence for oxidative phosphorylation in this cytochromeless species. With mannitol as the substrate, an aerobic Y of 64.6 was obtained. Extracts of mannitol-grown cells contained a nicotinamide adenine dinucleotide (NAD)-linked mannitol-1-phosphate (M-1-P) dehydrogenase. The difference in aerobic Y values with mannitol and glucose as substrates would indicate that the in vivo P/O ratio from the oxidation of reduced NAD generated by the oxidation of M-1-P approximates 0.6. The Y values with pyruvate and glycerol as substrates under aerobic conditions were 15.5 and 24.7, respectively.

Adenosine Triphosphate↗