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PubMed1996

Effect of polyunsaturated fatty acids deficiency on oxidative phosphorylation in rat liver mitochondria.

Liver mitochondria isolated from controls or polyunsaturated fatty acid (PUFA) deficient rats were studied for oxidative phosphorylation. A PUFA-deficient diet led to a dramatic change in the fatty acid composition of mitochondrial lipid content, similar to that reported in the literature. Besides the changes in lipid composition, mitochondrial volume was enlarged (+45% in state 4 and two-fold in state 3). State 4 respiration was increased together with a decrease in protonmotive force. The non-ohmicity of the relationship between non-phosphorylating respiration and protonmotive force was more pronounced in the PUFA-deficient group. State 3 oxygen consumption as well as the rate of ATP synthesis showed no difference between the two groups, whereas the protonmotive force decreased substantially in mitochondria from PUFA-deficient animals. In contrast, ATP/O ratios were decreased in the PUFA-deficient group when determined at subsaturating ADP concentration. Taken together, these results are in agreement with both an increased non-ohmic proton leak and an increased redox slipping. The relative importance of these two effects on the overall efficiency of oxidative phosphorylation depends on both the rate of oxidative phosphorylation and the maintained protonmotive force. Hence, in isolated mitochondria the respective role of each effect may vary between state 4 and state 3.

Adenosine Triphosphate↗

PubMed1998

Respiration and oxidative phosphorylation in the apicomplexan parasite Toxoplasma gondii.

Respiration, oxidative phosphorylation, and the mitochondrial membrane potential (DeltaPsi) of tachyzoites of the apicomplexan parasite Toxoplasma gondii were assayed in situ using very low concentrations of digitonin to render their plasma membrane permeable to succinate, ADP, safranin O, and other small molecules. The rate of basal respiration was slightly increased by digitonin when the cells were incubated in medium containing succinate. ADP promoted an oligomycin-sensitive transition from resting to phosphorylating respiration. Respiration was sensitive to antimycin A and cyanide, and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was oxidized by antimycin A-poisoned mitochondria. The addition of ADP after TMPD/ascorbate also resulted in phosphorylating respiration. The antitoxoplasmosis drug atovaquone, at a very low concentration (0.03 microM), totally inhibited respiration and disrupted the mitochondrial membrane potential. Atovaquone was shown to inhibit the respiratory chain of T. gondii and mammalian mitochondria between cytochrome b and c1 as occurs with antimycin A1. Phosphorylation of ADP could not be obtained in permeabilized tachyzoites in the presence of either pyruvate, 3-oxo-glutarate, glutamate, isocitrate, dihydroorotate, alpha-glycerophosphate, or endogenous substrates. Although ADP phosphorylation was detected in the presence of malate, this activity was rotenone-insensitive and was probably due to the conversion of malate into succinate through a fumarate reductase activity that was detected in mitochondrial extracts. Together these results provide the first direct biochemical evidence that the respiratory chain and oxidative phosphorylation are functional in apicomplexan parasites, although the terminal respiratory pathway is different from that in the mammalian host.

Animals↗

PubMedDate not supplied

Oxidative phosphorylation in rat liver mitochondria: influence of physical parameters.

Effects of pH, temperature, ionic strength and osmotic pressure on various respiratory states and indices of oxidative phosphorylation in well coupled rat liver mitochondria have been studied. It appears that temperature and osmotic pressure are the most important physical variables, whereas ionic strength and pH were devoid of any significant influence on oxidative phosphorylation. Thus any model for oxidative phosphorylation must critically account for the differential osmotic sensitivity of respiration as well as the curious fact that ADP/O ratio increases as temperature decreases.

Animals↗

PubMed2006

Critical role for mitochondrial oxidative phosphorylation in the activation of tumor suppressors Bax and Bak.

BACKGROUND: Activation of Bax and Bak, which act to permeabilize the mitochondrial membrane, is an essential step in the cell death response and therefore in the suppression of tumorigenesis. However, the mechanisms that regulate activation are poorly understood. METHODS: Bax and Bak activation (conformational change and dimerization) was monitored in Rat-1 fibroblasts and human cancer cells subjected to endoplasmic reticulum (ER) stress, DNA damage, or tumor necrosis factor-alpha (TNF-alpha) treatment. Pharmacologic inhibitors of reactive oxygen species production, electron transport in the respiratory chain, oxidative phosphorylation, and appropriate controls were used to identify potential modes by which Bax and Bak activation and the cell death response are controlled. The oligomerization state of Bax and Bak was determined by cross-linking and subsequent immunoblot analysis; Bax conformational change was analyzed by immunoprecipitation and immunoblotting with an antibody specific for the active conformation. Cell death was evaluated by dye exclusion. RESULTS: In both fibroblasts and human cancer cells subjected to cell death stimuli, inhibition of oxidative phosphorylation by use of antimycin A or oligomycin prevented ER stress-, DNA damage-, and TNF-alpha-induced Bax and Bak activation and cell death (UV-induced Rat-1 cell death at 15 hours: control, mean = 33.6%, 95% confidence interval [CI] = 18.8% to 48.4%; antimycin A, mean = 10.0%, 95% CI = 0% to 21.7%; oligomycin, mean = 13.1%, 95% CI = 5.7% to 20.5%; tunicamycin-induced MCF-7 cell death at 9 hours: control, mean = 29.2%, 95% CI = 21.6% to 36.8%; antimycin A, mean = 15.3%, 95% CI = 0.8% to 29.8%; oligomycin, mean = 11.5%, 95% CI = 3.9% to 19.1%; TNF-alpha-induced MCF-7 cell death at 6 hours: control, mean = 24.0%, 95% CI = 12.6% to 35.4%; antimycin A, mean = 8.9%, 95% CI = 3.9% to 13.9%; oligomycin, mean = 13.3%, 95% CI = 10.4% to 16.2%). Increasing and decreasing glycolytic adenosine triphosphate production, by adding glucose and 2-deoxy-D-glucose to the cell growth medium, respectively, neither reversed nor recapitulated, respectively, the effect of compromised oxidative phosphorylation on Bax and Bak activation. CONCLUSION: Oxidative phosphorylation is required for the activation of Bax and Bak and cell death triggered by disparate death stimuli. The reliance of tumor cells on glycolysis in preference to oxidative phosphorylation even under normoxic conditions (Warburg effect) may therefore be a potential means by which these cells evade programmed cell death.

Animals↗

PubMed1988

Unique action of a modified weakly acidic uncoupler without an acidic group, methylated SF 6847, as an inhibitor of oxidative phosphorylation with no uncoupling activity: possible identity of uncoupler binding protein.

The potent weakly acidic uncoupler SF 6847 was modified by methylation of its phenolic OH group, and the effect of the resulting derivative, with no acid-dissociable group, on oxidative phosphorylation in rat liver mitochondria was examined. The methylated SF 6847 did not induce uncoupling at up to 40 microM, while SF 6847 uncoupled oxidative phosphorylation completely at about 20 nM, indicating that the acid-dissociable group is essential for uncoupling. The O-methylated SF 6847 at 20 microM did, however, inhibit state 3 respiration of mitochondria, although it did not inhibit electron-flow through the respiratory chain, ATPase activated by weakly acidic uncouplers or Pi-ATP exchange. At the same concentration, it also inhibited ATP synthesis in submitochondrial particles. These features are different from those of known inhibitors of oxidative phosphorylation. Thus, O-methylated SF 6847 is a unique inhibitor of oxidative phosphorylation. The possible identity of the uncoupler binding protein is discussed on the basis of these results.

Adenosine Triphosphate↗

PubMed2000

Oxygen consumption measurement in lymphocytes for the diagnosis of pediatric patients with oxidative phosphorylation diseases.

OBJECTIVES: To evaluate the results of oxygen consumption measurement in lymphocytes for the diagnosis and treatment monitoring of pediatric patients with oxidative phosphorylation diseases. DESIGN AND METHODS: Twenty-four children with an oxidative phosphorylation disease were studied. Results were compared with those of 87 healthy children. Oxygen consumption measurements in digitonine-permeabilized lymphocytes incubated with pyruvate plus malate and succinate were performed in a Clark-type oxygen electrode. RESULTS: A total of 58% of patients showed a decreased oxygen consumption in lymphocytes incubated with pyruvate. In 4 patients, this analysis was the unique initial biochemical test, which revealed an impaired mitochondrial energy metabolism. Significant differences were observed in lymphocytes incubated with pyruvate between patients and reference values (p<0.00005), and in lymphocytes incubated with pyruvate before and after treatment (p<0.05). CONCLUSIONS: This test is useful for diagnosing oxidative phosphorylation diseases in patients who did not have other biochemical alterations, although false-negative results can be found. It is not useful for treatment monitoring.

Adolescent↗

PubMed1967

Properties of substituted 2-trifluoromethylbenzimidazoles as uncouplers of oxidative phosphorylation.

1. The activity of 25 substituted 2-trifluoromethylbenzimidazoles in uncoupling oxidative phosphorylation by rat-liver mitochondria has been compared. 2. For halogen- or mixed-halogen- and alkyl-substituted analogues, uncoupling activity was proportional to the acidity of the imidazole -NH group. Tetrachloro-2-trifluoromethylbenzimidazole was the most active (50% uncoupling of oxidative phosphorylation at 7.9x10(-8)m, pK5.04). Nitro-substituted analogues were less active than predicted from pK considerations or from partition-coefficient measurements. 3. Introduction of an -NH(2) or -CO(2)H substitutent caused a loss of uncoupling activity, as did alkylation at position 1 of the imidazole ring. 4. Benzimidazoles active as uncouplers stimulated mitochondrial adenosine triphosphatase but not all stimulated the oxidation of succinate in the absence of a phosphate acceptor. 5. 4,5-Dichloro-2-trifluoromethylbenzimidazole inhibited the succinate-oxidase system at about the same concentration required for uncoupling (0.52mum for 50% inhibition of both activities) and the site of this inhibition appears to lie between succinate dehydrogenase and cytochrome b.

Animals↗

PubMed2003

Metabolic network control of oxidative phosphorylation: multiple roles of inorganic phosphate.

Phosphate (Pi) is a putative cytosolic signaling molecule in the regulation of oxidative phosphorylation. Here, by using a multiparameter monitoring system, we show that Pi controls oxidative phosphorylation in a balanced fashion, modulating both the generation of useful potential energy and the formation of ATP by F1F0-ATPase in heart and skeletal muscle mitochondria. In these studies the effect of Pi was determined on the mitochondria [NADH], NADH generating capacity, matrix pH, membrane potential, oxygen consumption, and cytochrome reduction level. Pi enhanced NADH generation and was obligatory for electron flow under uncoupled conditions. Pi oxidized cytochrome b (cyto-b) and reduced cytochrome c (cyto-c), potentially improving the coupling between the NADH free energy and the proton motive force. The apparent limitation in reducing equivalent flow between cyto-b and cyto-c in the absence of Pi was confirmed in the intact heart by using optical spectroscopic techniques under conditions with low cytosolic [Pi]. These results demonstrate that Pi signaling results in the balanced modulation of oxidative phosphorylation, by influencing both deltaGH+ generation and ATP production, which may contribute to the energy metabolism homeostasis observed in intact systems.

Adenosine Diphosphate↗

PubMed1996

Dependence of flux size and efficiency of oxidative phosphorylation on external osmolarity in isolated rat liver mitochondria: role of adenine nucleotide carrier.

The aim of this work was a thermodynamic and kinetic study of the influence of varying external osmolarity on overall oxidative phosphorylations in isolated rat liver mitochondria. When external osmolarity is increased from 100 to 400 mosM by using a non-penetrant sugar: (i) matrix volume diminishes, (ii) state 3 respiratory rate decreases when state 4 slightly varies, (iii) states 3 and 4 protonmotive force and NAD(P)H level increase, whereas oxidative phosphorylation efficiency (ATP/O) decreases. Indeed, respiratory flux versus protonmotive force relationships depend on the osmolarity considered: the lower the external osmolarity, the higher the span of overall driving force necessary for the same respiratory rate. To further investigate the mechanism of the decrease in respiratory and ATP synthesis flux leading to a lowering in oxidative phosphorylation efficiency, we determined the adenine nucleotide carrier control coefficient on respiratory and ATP synthesis rates respectively. The main result is that the adenine nucleotide carrier control coefficient on respiratory rate decreases, and conversely that adenine nucleotide carrier control on ATP synthesis rate increases, from iso- to hyperosmolarity. Furthermore, whatever the osmolarity, when state 3 respiratory rate is titrated with carboxyatractyloside, the same relationship is observed between ATP/O ratio and respiratory flux. From many previous studies, it has been shown that an increase in external osmolarity and a consequent decrease in matrix volume inhibits almost all mitochondrial proton pumps (coupling site 1 and 2 of respiratory chain, ATPase) in different ways. In this work, we show that in phosphorylating mitochondria, the adenine nucleotide carrier plays a key role: its inhibition as the external osmolarity increases lowers the state 3 respiration close to state 4 level and consequently leads to a decrease in oxidative phosphorylation efficiency.

Adenosine Triphosphate↗

PubMedDate not supplied

[Oxidative phosphorylation in rat heart mitochondria under administration of hydrocortisone and insulin].

The rate of oxidative phosphorylation was studied in heart mitochondria of rats which were administered hydrocortisone and then corticoid in combination with insulin. It is established that 5 h after a single administration of hydrocortisone oxidative phosphorylation increases slightly and is statistically insignificant. Injections of corticosteroids to animals for 14 days inhibit considerably the rate of oxidation and phosphorylation, cause a decrease in the values of respiratory control and APD/O coefficient. Administration of insulin simultaneously with hydrocortisone to animals normalizes these disturbances to a considerable extent.

Animals↗

PubMed2000

Oxidative phosphorylation in cardiolipin-lacking yeast mitochondria.

The role of cardiolipin in mitochondrial energy transformation was studied by comparing oxidative phosphorylation in the Saccharomyces cerevisiae cardiolipin synthase null mutant crd1Delta, and in isogenic wild type. Oxygen consumption experiments and membrane potential kinetics during the phosphorylation cycle in isolated mitochondria indicated that the absence of cardiolipin causes only a moderate deficiency of mitochondrial energy-transforming machinery at 25 degrees C. However, at 40 degrees C, respiration was completely uncoupled from phosphorylation for the mutant mitochondria, in contrast with that for the wild-type. Membranepotential kinetics demonstrated an increased susceptibility of the mutant mitochondria to gradual deterioration during in vitro incubation. These results suggest that cardiolipin, although normally associated with several of the major enzymes of oxidative phosphorylation and required in vitro for their maximal activity, is not absolutely necessary for mitochondrial energy transformation under optimal conditions. The role of cardiolipin is, rather, to improve efficiency of oxidative phosphorylation and its resistance to unfavourable conditions, such as increased temperature.

Adenosine Triphosphate↗

PubMedDate not supplied

[The effect of low concentrations of sodium nitrites and nitrates on respiration and oxidative phosphorylation in rat liver mitochondria].

Nitrite incubation in mitochondria and nitrate intoxication of rats have been studied for their effect on aerobic energetic processes in the liver. Sodium nitrite in concentration of 2 mg/l causes an inhibition of ADP-stimulated respiration and provides uncoupling processes of oxidative phosphorylation and respiration in mitochondria, when adding succinate as a substrate. Low doses of nitrate in vivo promote oxygen economization in mitochondria. Intoxication of rats with nitrate in a dose of 50 mg/l for 30 days induces a decrease of the respiration rate after ADP-phosphorylation and an increase of the coefficient of oxidative phosphorylation efficiency (ADP/O). Intraperitoneal administration of adrenalin in a dose of 25 micrograms/100 g to rats after 30-day nitrate intoxication in a concentration of 10 mg/l induces no typical increase of ADP-stimulated respiration and rate of oxidative phosphorylation and succinate oxidation.

Animals↗

PubMed1999

Mitochondrial oxidative phosphorylation in heart from stressed cardiomyopathic hamsters.

Stress alone is generally not sufficient to produce serious disease, but stress imposed upon pre-existing disease can contribute to disease progression. To explore this phenomenon, cold-immobilization stress was imposed on young 12.5 month, necrotic phase with small vessel coronary spasm) and older (5 month, quiescent phase, between necrosis and heart failure) cardiomyopathic hamsters. Our hypothesis was that changes in mitochondrial energy processes are involved in stress induced pathology. Polarographic and high performance liquid chromatography (HPLC) techniques were used to measure mitochondrial respiration and oxidative phosphorylation and concentrations of phosphocreatine and adenylates, respectively, in hearts from young and old cardiomyopathic hamsters (stressed and unstressed). No significant differences were found between the young (2.5 month) and old (5 month) age groups in unstressed and stressed healthy hamsters and between young (2.5 month) and old (5 month) unstressed cardiomyopathic hamsters with respect to different parameters of mitochondrial oxidative phosphorylation and with respect to concentration of bioenergetic metabolites, except that ADP concentration was higher in older cardiomyopathic hamsters. Application of stress uncovered differences between young and old cardiomyopathic hamsters: respiration control index was lower and State 4 respiration was higher in young compared to old cardiomyopathic hamsters; whereas the total concentration of ATP was decreased to the same level in both cardiomyopathic groups when compared to control. Mitochondrial oxidative phosphorylation in young cardiomyopathic hamsters was more sensitive to Ca2+, as evidenced by partial uncoupling of respiration and oxidative phosphorylation, than in older cardiomyopathic hamsters and controls. In conclusion, young cardiomyopathic hamsters, i.e. in the necrotic phase of disease, were more susceptible to stress induced changes in mitochondrial oxidative phosphorylation than older cardiomyopathic hamsters and controls.

Age Factors↗

PubMed2005

Delayed metabolic activation of oxidative phosphorylation in skeletal muscle at exercise onset.

In "normal" conditions (e.g., normoxia, absence of pathological conditions) convective and diffusive O(2) delivery to skeletal muscle fibers do not seem to represent important determinants for the kinetics of adjustment of oxidative phosphorylation following increases in metabolic demand. Whereas a limiting role by PDH has not been experimentally confirmed, inhibition of mitochondrial respiration by NO could be partially responsible for the delayed activation of oxidative phosphorylation at exercise onset. The main determinants of muscle VO(2) kinetics, however, likely reside in the intricate interplay between the various mechanisms of energy provision at exercise onset. By acting as high-capacitance energy buffers, PCr hydrolysis and anaerobic glycolysis would delay or attenuate the increase in [ADP] within the cell following rapid increases in ATP demand, thereby "buffering" a more rapid activation of oxidative phosphorylation. The "PCr-Cr shuttle" concept of a regulatory role of PCr or of the products of PCr hydrolysis on oxidative phosphorylation provides a mechanism that couples VO(2), which occurs in mitochondria, to PCr hydrolysis occurring in the cytoplasm.

Cell Respiration↗

PubMed1980

Restoration of active transport of solutes and oxidative phosphorylation by naphthoquinones in irradiated membrane vesicles from Mycobacterium phlei.

Irradiation of the inverted membrane vesicles of Mycobacterium phlei with light at 360 nm inactivated the natural menaquinone [MK(9)(II-H)] and resulted in a loss of substrate oxidation, pH gradient, membrane potential, active transport of proline or calcium ions, and oxidative phosphorylation. Restoration of the protonmotive force and active transport occurred on addition of naphthoquinones such as vitamin K(1), menadione, or lapachol to the irradiated membrane vesicles. However, coupled phosphorylation was restored only by vitamin K(1). Menadione and lapachol did not act as uncoupling agents. The magnitude of the pH gradient and membrane potential in the quinone-restored system was a reflection of the rate of oxidation and was correlated with the rate of uptake of proline or Ca(2+). These results are consistent with the chemosmotic hypothesis proposed for the energy transducing mechanism for active transport and further demonstrate that the complete respiratory chain is not required to drive active transport. In contrast, the data suggest that in addition to the driving force (protonmotive force) necessary to establish oxidative phosphorylation, a specific spatial orientation of the respiratory components, such as the naphthaquinones, is essential for the utilization of the proton gradient or membrane potential or both. Bypass of electrons from the respiratory chain with menadione may explain the inability of this quinone to restore oxidative phosphorylation; however, lapachol restores oxidation by the same electron transport pathway as the natural menaquinone but fails to restore phosphorylation. Because all three quinones restore the protonmotive force, other factors that are discussed must be considered in understanding the mechanism of oxidative phosphorylation.

Biological Transport, Active↗

PubMed1992

Several nongenotoxic carcinogens uncouple mitochondrial oxidative phosphorylation.

A number of plasticizers and lipid-lowering drugs induce peroxisomes and cause hepatocellular carcinoma in rodents by mechanisms which remain unknown. In this study, seven structurally dissimilar peroxisome proliferating agents were shown to uncouple oxidative phosphorylation in isolated rat liver mitochondria. For example, perfluorooctanoate (0.5 mM) increased succinate-induced (state 4) mitochondrial respiration by over 50% while stimulation of state 3 respiration with ADP was minimal (i.e., uncoupling occurred). Interestingly, compounds which are potent carcinogens in vivo (e.g., Wy-14,643 and perfluorooctanoate) were more powerful uncouplers of oxidative phosphorylation in vitro than weak tumor-causing agents (e.g., valproate). Uncoupling also occurred in vivo. Basal rates of oxygen uptake in perfused livers from chronically treated rats were increased from 137 +/- 7 mumol g-1/h in pair-fed controls to 153 +/- 5 mumol g-1/h after 2.5 months of feeding Wy-14,643 (0.1% w/v in diet). Concomitantly, rates of urea synthesis from ammonia, a process highly dependent on ATP supply, were reduced almost completely from 104 +/- 10 mumol g-1/h to 13 +/- 6 mumol g-1/h. Bile flow, another energy-dependent process, was also reduced significantly by treatment with Wy-14,643 in vivo for 24 h. Taken together, these data indicate that energy supply for cellular processes such as urea synthesis and bile flow was disrupted in vivo due to uncoupling of oxidative phosphorylation by Wy-14,643. It is proposed that peroxisomal proliferators accumulate in the liver where they uncouple mitochondrial oxidative phosphorylation and interfere with cellular energetics.

Animals↗

PubMed1972

An adenosine triphosphate-phosphate exchange catalyzed by a soluble enzyme couple inhibited by uncouplers of oxidative phosphorylation.

The sulfenic acid form of glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12), which is an acyl phosphatase, will catalyze an acetyl phosphate-Pi exchange reaction. This exchange reaction is reversibly inhibited by the uncouplers of oxidative phosphorylation, 2,4-dinitrophenol, m-Cl carbonylcyanide-phenylhydrazone, pentachlorophenol, and 5-chloro-3-tert-butyl-2'-chloro-4'-nitrosalicylanalide, and is irreversibly inhibited by cyanide and dicumarol. An ATP-Pi exchange reaction similar to that catalyzed by mitochondria can be simulated by a system composed of oxidized glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase (EC 2.7.1.28), 3-phosphoglycerate, ATP, (32)Pi, and appropriate cofactors. The ATP-Pi exchange is inhibited by uncouplers of oxidative phosphorylation. Higher concentrations of uncouplers will also inhibit the ATPase reaction catalyzed by the coupled enzyme system. The exchange reactions catalyzed by the sulfenic acid form of glyceraldehyde-3-phosphate are consistent with a sulfenyl carboxylate intermediate. On the basis of these observations, a reaction scheme has been postulated for covalent coupling in oxidative phosphorylation that includes a sulfenyl carboxylate as a nonphosphorylated, high energy intermediate and an acyl phosphate as a phosphorylated, high energy intermediate.

Adenosine Triphosphate↗

PubMed1985

Pyruvate-dependent oxidative phosphorylation in erythroid and myeloid tumor mitochondria.

The pyruvate-supported oxidative phosphorylation activity was determined in mitochondria isolated from the fast-growing erythroid and myeloid tumors of hematopoietic origin. Normal bone marrow and liver mitochondria were used for comparison. In the absence of primers, both tumor mitochondria exhibited a pyruvate-dependent respiratory state 4/state 3 transition, which was totally inhibited by either alpha-cyanocinnamate or arsenite. The transition rate increased in a concentration-dependent manner from 5 to 100 microM pyruvate, where the maximum activity was reached. Increasing the concentration to 500 microM and beyond, however, resulted in decreasing state 3 respiratory jump with little or no jump demonstrable at concentrations above 5 mM. Moreover, the addition of high concentrations of pyruvate during the respiratory state 3 caused a blockage of that state which was reestablished by the addition of succinate or alpha-ketoglutarate. These results clearly show the capacity of erythroid and myeloid tumor mitochondria to actively utilize low concentrations of pyruvate to support their oxidative phosphorylation activity. The reason for the absence of activity found with the high concentration, however, is not readily apparent.

Animals↗