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PubMed1970

A dynamic stereochemical reaction mechanism for the ATP synthesis reaction of mitochondrial oxidative phosphorylation.

A mechanism is presented for the ATP synthesis reaction of mitochondrial oxidative phosphorylation. This mechanism is a dynamic, stereospecific, microscopically reversible mechanism in which enzyme-bound substrates, ADP, and inorganic phosphate directly combine in a S(N)2 type of process which proceeds with retention of configuration at the phosphate phosphorus center. The mechanism involves unstable, pentacovalent trigonal bipyramidal reaction intermediates which are pseudorotationally related. The mechanism accounts for all of the observed net and equilibrium exchange reactions and their relative rates. All of the exchange reactions are directly referrable to the ATP synthesis mechanism, and are circumstantial traits of that mechanism.

Adenosine Triphosphate↗
PubMed1993

A benzopyrylium dye as a novel effective cationic uncoupler of oxidative phosphorylation.

Benzopyrylium dye BDBP was found to be an effective uncoupler of oxidative phosphorylation. It stimulates state 4 respiration of mitochondria 2-fold at about 2 microM, reveals a maximum stimulation (8-fold) at 30 microM and inhibits the respiration at higher concentrations. BDBP is also an effective proton (hydroxyl) carrier through bilayer lipid membranes (BLM) as is seen from the electrical properties of BLM with BDBP. Picrate enhances the effects of BDBP on the mitochondrial respiration and BLM conductance. The BDBP activities are accounted for by formation of dimers and complexes with picrate.

Animals↗
PubMed2004

Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1.

The long-lived mutant of Caenorhabditis elegans, clk-1, is unable to synthesize ubiquinone, CoQ(9). Instead, the mutant accumulates demethoxyubiquinone(9) and small amounts of rhodoquinone(9) as well as dietary CoQ(8). We found a profound defect in oxidative phosphorylation, a test of integrated mitochondrial function, in clk-1 mitochondria fueled by NADH-linked electron donors, i.e. complex I-dependent substrates. Electron transfer from complex I to complex III, which requires quinones, is severely depressed, whereas the individual complexes are fully active. In contrast, oxidative phosphorylation initiated through complex II, which also requires quinones, is completely normal. Here we show that complexes I and II differ in their ability to use the quinone pool in clk-1. This is the first direct demonstration of a differential interaction of complex I and complex II with the endogenous quinone pool. This study uses the combined power of molecular genetics and biochemistry to highlight the role of quinones in mitochondrial function and aging.

Animals↗
PubMed1976

Studies on oxidative phosphorylation and steroidogenesis by ovarian mitochondria after gonadotropic stimulation.

No differences in oxidative phosphorylation or in the per cent of [4-14C]progesterone were found in ovarian mitochondria of immature rats after treatment with 20 IU of pregnant mare serum gonadotropin (PMSG) iv 30 min before killing. However, treatment of immature rats with 20 IU of PMSG sc 54 h prior to killing decreased the ADP:O ratio and increased the per cent of [4-14C]cholesterol conversion. Electron microscopic studies showed that mitochondria with lamellar cristae were prominent in ovaries of untreated rats, while large pleomorphic mitochondria and mitochondria with tubulovesicular cristae dominated in ovaries of PMSG-treated rats. Ovarian homogenates separated by zonal centrifugation showed three peaks od cytochrome oxidase activity which shifted to the heavier end of the gradient after PMSG treatment. These studies suggest that PMSG treatment influences ovarian mitochondria, possibly by stimulating the synthesis of additional functional components and/or the biogenesis of new mitochondria. Aminoglutethimide addition to bovine luteal mitochondria decreased steroidogenesis by 60% when succinate was used as substrate. However, there was a 16% increase in the ADP:O ratio, apparently due to a decrease in oxygen utilization. When oligomycin was added to luteal mitochondria, there was a 30% decrease in the ACP:O ratio but a 300% increase in [4-14C]cholesterol conversion. Dinitrophenol also decreased mitochondrial steroidogenesis. These results suggest that energy obtained from succinate oxidation can be diverted from phosphorylation to support steroidogenesis.

Age Factors↗
PubMed1985

[The mechanism of action of E.coli endotoxin on oxidative phosphorylation of the rat liver mitochondria].

The effects of E.coli endotoxin on oxidative phosphorylation were investigated in vitro using isolated rat liver mitochondria. The respiratory control index (RCI) was significantly decreased by preincubation of mitochondria for 20 min. at 30 degrees C in the presence of the endotoxin, which repressed dose-dependently the state 3 respiration. The extent of the repression of this state 3 respiration was comparable with that of the exchange reaction of adenine nucleotide. The endotoxin, however, did not inhibit several mitochondrial enzymes including the electron transport system at the enzyme level. The exchange reaction and the number of the ADP-binding sites of the adenine nucleotide carrier were assayed using [14C] ADP and [3H] carboxyatractyloside, respectively. The exchange reaction was repressed by 72% and the number of binding site of carboxyatractyloside was decreased by 20% by the endotoxin (100 micrograms/mg mitochondrial protein). These effects of endotoxin on the adenine nucleotide carrier were additionally enhanced by the Ca2+ ion. The occurrence of these effects was prevented by EGTA or dibucaine, a potent inhibitor of phospholipase A2. These results suggested that the endotoxin may activate phospholipase A2 which may harm the lipid layer of the mitochondrial membrane.

Animals↗
PubMed1970

Oxidative phosphorylation. The specific binding of trimethyltin and triethyltin to rat liver mitochondria.

1. The binding of trimethyltin and triethyltin to rat liver mitochondria was determined and the results were analysed by the method of Scatchard (1949). 2. One binding site (site 1) has the correct characteristics for the site to which trimethyltin and triethyltin are attached when they inhibit oxidative phosphorylation. For each compound the concentration of site 1 is 0.8nmol/mg of protein and the ratios of their affinity constants are the same as the ratio of the concentrations inhibiting oxidative phosphorylation. 3. Binding site 1 is present in a fraction derived from mitochondria containing only 15% of the original protein. In this preparation ultrasonication rapidly destroyed site 1. 4. Dimethyltin and diethyltin do not prevent binding of triethyltin to rat liver mitochondria, whereas triethyl-lead does. 5. Trimethyltin and triethyltin bind to mitochondria from brown adipose tissue and the results indicate a binding site 1 similar to that in rat liver mitochondria. 6. The advantages and limitations of this approach to the study of inhibitors are discussed.

Adipose Tissue, Brown↗
PubMed1984

Alterations of oxidative phosphorylation reactions in mitochondria isolated from hypothyroid rat liver.

Several parameters of oxidative phosphorylation reaction were studied in vitro in isolated liver mitochondria from hypothyroid rats. When succinate was employed as a respiratory substrate for mitochondria incubated in a mannitol/sucrose/phosphate buffer, and measurements were performed during initial additions of ADP, the magnitude of state 3 and state 4 respiration was not different between mitochondria from the hypothyroid and those from the control rats. During the course of repetitive additions of ADP and consequently of sequential transitions from state 4 to state 3 and back to state 4, mitochondria from hypothyroid animals showed a gradual decline in the rate of both state 3 and state 4 respiration whereas those from normal animals did not. The total succinate dehydrogenase activity was not different between the two types of mitochondria, and the decline in state 3 and state 4 respiration was not accompanied by any change in the apparent Km for ADP or in the corrected ADP/O ratio [Biochem. Biophys. Res. Commun. (1973) 53, 988]. The amount of oxygen consumed during the state-4----3----4 transition was lower in the hypothyroid than in the control mitochondria. These alterations were reversed if the hypothyroid animals were injected with thyroxine intraperitoneally (2 micrograms/100 g body weight) for 3 weeks before isolation of mitochondria. These results indicate that the fall of respiratory activity in hypothyroidism may result from the decrease not only of respiratory activities of state 3 and state 4, but also of the energy spent in the process of the state-4----3----4 transition, while the coupling efficiency per se remains normal. These properties become manifest when mitochondria respond to pulses of ADP load, a situation likely to occur in situ.

Adenosine Diphosphate↗
PubMed2004

Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders.

Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

Adenosine Triphosphate↗
PubMed1976

Oxidative phosphorylation in Micrococcus denitrificans: calculation of the P/O ratio in growing cells.

P/O ratios were measured in membrane particles obtained from cells of Micrococcus denitrificans, while growing on different carbon sources. The membrane particles obtained from cells growing actively on glucose, succinate, ethanol and propanol as the carbon and energy sources catalyzed oxidative phosphorylation and yielded respective P/O ratios of 1.4, 1.2, 0.8, and 0.5 with NADH, and 0.8, 0.6, 0.6, and 0.5 with succinate as the electron donors. Not such a difference in P/O ratio is observed in intact resting cells grown with different carbon sources. It is concluded that the influence of the carbon source is probably directed towards the efficiency of oxidative phosphorylation in membrane particles and not in the growing cells. For the aerobic carbon source-limited chemostat cultures the following maximum growth yields were determined: 40.2 and 34.2 for succinate and oxygen, 41.7 and 36.5 for malate and oxygen, 81.4 and 39.4 for mannitol and oxygen, and 77.8 and 43.4 for gluconate and oxygen respectively. With a mathematical model (de Kwaadsteniet et al., in press) the P/O ratio was valued at 1.4-1.7. YATP at mu=0.2 was valued at 8.7-10.9; YmaxATP at 9.6-13.2 and me at 0.6-4.5 for the most precise experiment (gluconate-limited). The calculation of these growth parameters has been discussed.

Aerobiosis↗
PubMed2000

Effect of linear polarized light radiation on impaired mitochondrial oxidative phosphorylation in skeletal muscle.

PURPOSE: The aim of this study was to investigate the effect of linear polarized light radiation (LPLR) on mitochondrial oxidative phosphorylation impaired by hemorrhagic shock or Escherichia coli lipopolysaccharide (LPS) in skeletal muscle. METHODS: We studied the effect of LPLR on mitochondrial function of skeletal muscle by using a model of mitochondria impaired by hemorrhage or LPS. The oxygen uptake in states 3 and 4, the respiratory control ratio (RCR), and the adenosine diphosphate-to-oxygen ratio (ADP/O) were measured with a Clark oxygen electrode. RESULTS: Oxygen uptake in states 3 and 4, RCR, and ADP/O were significantly decreased by hemorrhage for 4 h and by LPS treatment for 12 h. Oxygen uptake in states 3 and 4 impaired by hemorrhage increased significantly from 40.1 +/- 3.2 to 60.1 +/- 5.4 nmol O(2).min(-1).mg protein(-1) after LPLR, and oxygen uptake in state 4 decreased significantly from 22.8 +/- 2.4 to 17.7 +/- 1.5 nmol O(2).min(-1).mg protein(-1) after LPLR. RCR and ADP/O were also significantly increased from 1.8 +/- 0.3 and 0.9 +/- 0.2 to 3.4 +/- 0.3 and 1.5 +/- 0.1, respectively, by LPLR. Oxygen uptake in states 3 and 4 impaired by LPS was improved from 46.6 +/- 5.1 and 21.0 +/- 1.9 to 53.8 +/- 6.2 and 17.9 +/- 2.3 nmol O(2).min(-1).mg protein(-1), respectively following LPLR. RCR and ADP/O were also elevated significantly from 2.2 +/- 0.2 and 0.9 +/- 0.2 to 3.0 +/- 0.3 and 1.4 +/- 0.2, respectively, after LPLR. CONCLUSION: LPLR improved mitochondrial oxidative phosphorylation of skeletal muscle impaired by hemorrhagic shock or E. coli LPS.

Journal Article↗
PubMedDate not supplied

[Effect of digoxin, strophanthin and isolanid on oxygen absorption, oxidative phosphorylation and the amount of cytochromes in the myocardial mitochondria and their ATPase activity].

A total of 200 nonlinear rats were used to study the release and utilization of energy in the normal myocardium on administration of clinical concentrations of cardiac glycosides. It was found that cardiac glycosides exert no effect on oxidative phosphorylation under utilization of alpha-ketoglutarate. At the same time digoxin and strophanthin ( to a less degree) intensify the phosphorylating activity of mitochondria, while isolanid has no effect on the oxidative and phosphorylating activity under oxidation of succinate. The content of the enzymes in the terminal portion of the respiratory chain, namely the myocardial mitochondria - cytochromes, did not change under the effect of cardiac glycosides. The test animals were shown to have an increased activity of actomyosin ATPase.

Actomyosin↗
PubMed1999

Activation of Glut1 glucose transporter in response to inhibition of oxidative phosphorylation.

We have previously shown that exposure of Clone 9 cells to hypoxia, cyanide, or azide results in an acute stimulation of glucose transport that is largely mediated by "activation" of glucose transporter (Glut1) sites preexisting in the plasma membrane. However, it is not known whether inhibition of oxidative phosphorylation only at its terminal step, or at any of its steps, leads to the glucose transport response. Hence, the effect of azide (5 mM), rotenone (1 microM), rotenone (1 microM) plus thenoyltrifluoroacetone (TTFA) (5 microM), antimycin A (0.3 microM), dinitrophenol (0.25 mM), carbonyl cyanide m-chlorophenylhydrazone (CCCP) (2.5 microM), and oligomycin B (0.15 microM) on glucose transport was determined. All of the above agents elicited a similar approximately 4-fold stimulation of cytochalasin B (CB)-inhibitable 3-O-methyl glucose (3-OMG) uptake in Clone 9 cells. The stimulatory effect of azide on 3-OMG uptake was not inhibited by antioxidants 2-mercaptopropionyl glycine (1.2 mM) and 1,10-phenanthroline (40 microM), while, in contrast, the antioxidants attenuated the stimulation of glucose transport in response to 250 microM H(2)O(2) by approximately 50%. To differentiate between an increase in the number of functional Glut1 sites in the plasma membrane (in the absence of "translocation") versus an increase in the "intrinsic activity" of Glut1, the effect of azide on the energy of activation (E(a)) of glucose transport was measured. The E(a) was determined by measuring the rate of CB-inhibitable 3-OMG uptake at 24.0, 28.0, 35. 0, and 40 degrees C. The E(a) of control Clone 9 cells and of cells exposed to 10 mM azide for 2 h was 32,530 +/- 1830 and 31,220 +/- 600 J/mol, respectively (P > 0.1), while the rate of CB-inhibitable 3-OMG uptake was 9.3 +/- 0.7-fold higher in azide-treated cells. It is concluded that (i) inhibition of oxidative phosphorylation, at any of its steps, leads to a stimulation of glucose transport, and (ii) the mechanism of stimulation of glucose transport in response to azide appears to be predominately mediated by an apparent increase in the number of functional Glut1 sites in the plasma membrane (instead of an increase in their "intrinsic activity"), suggesting an "unmasking" mechanism.

Animals↗
PubMed1977

Mitochondrial membrane-linked reactions in carcinogenesis: change in steroselective uncoupling of oxidative phosphorylation by aliphatic dicarbonyls and in the Arrhenius plot of NADH-indophenol reductase.

The previously observed alterations in the energy transducing system of rat liver mitochondria during 3'-methyl-4-(dimethylamino)azobenzene (3'-Me-DAB) carcinogenesis were investigated using aliphatic dicarbonyl compounds as molecular probes and the effect of temperature on the membrane-linked NADH-indophenol reductase. The vicinal diketone, diacetyl, uncouples oxidative phosphorylation in normal rat liver mitochondria while the higher diketones, acetylacetone and acetonylacetone, are increasingly less effective in that order; diacetyl totally abolishes respiratory control with substrates the oxidation of which involves the NADH leads to CoQ segment, but only partially with succinate which bypasses this segment. Diacetyl, likewise, uncouples oxidative phosphorylation in liver mitochondria from rats fed 3'-Me-DAB, but the mitochondria are most resistant to this uncoupling (in terms of the P/O ratio) at the time period when the respiratory control index (determined in the absence of diacetyl) is at the dye-induced minmum. This time period is at 3 to 4 weeks of dye administration, representing the cumulative dose for tumorigenesis threshold. At this threshold period of feeding 3'-Me-DAB, discontinuities in the Arrhenius plot of the mitochondrial membrane-localized NADH-indophenol reductase appear, with a return toward the control state (no break) at 8 weeks, only to reappear in the plot of the enzyme from tumor mitochondria, suggesting sequential membrane phase transitions in the mitochondria during azo dye carcinogenesis.

2,6-Dichloroindophenol↗
PubMedDate not supplied

[Effect of ACTH, TTH, and STH on respiration and oxidative phosphorylation in the liver of hypophysectomized rats].

An experimental study was make of the changes in respiration and of the oxidative phosphorylation in the hepatic mitochondria of the hypophysectomized albino rats, with consideration to the regulatory effects of the ACTH, TTH, and STH. There was an intensification of the conjugation of the oxidative and of the phosphorylation processes in the mitochondria of the liver of hypophysectomized albino rats as a result of ACTH replacement therapy in a dose of 3 Units per 100 g of weight. TTH given in a dose of 0.03 IU per 100 g of weight under conditions of hypophysectomy stimulated oxidation of alpha-ketoglutaric acid in the mitochondria of the liver of albino rats; phosphorylation remained reduced, i.e. there was seen a dissociation of the process of oxidative phosphorylation. As a result of replacement therapy with the STH given in a dose of 10 gamma per 100 g of weight the energy metabolism in the liver of hypophysectomized albino rats changed in the direction of an increase in the P/O coefficient of the hepatic mitochondria. ACTH, TTH, and STH were given from the 15th to the 21st days after hypophysectomy, twice a day, subcutaneously.

Adrenocorticotropic Hormone↗
PubMed1990

Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation.

Since previous studies have suggested that the coupling of oxidation to phosphorylation is impaired in Alzheimer brain and fibroblasts, the effects of carbonyl cyanide m-chlorophenylhydrazone, a hydrazone known to uncouple mitochondrial oxidative phosphorylation, were tested on the development of immunoreactivity with antibodies to "Alzheimer antigens" in cultured fibroblasts from cognitively intact subjects. The fibroblasts were exposed for 10 to 14 days to a medium (DMd) modeled on media that favor neuronal differentiation in fetal brain cultures. The addition of a 10-microns concentration of carbonyl cyanide m-chlorophenylhydrazone to the DMd culture medium increased by more than 10-fold the proportion of cells reacting immunocytochemically with antibodies to paired helical filaments and by 157-fold the proportion of cells reacting with the Alz-50 monoclonal antibody. These observations suggest that the oxidative abnormalities previously described in tissues from patients with Alzheimer's disease may contribute to the accumulation of abnormal cytoskeletal materials in this disorder.

Aged↗
PubMed1996

Pentamidine is an uncoupler of oxidative phosphorylation in rat liver mitochondria.

Pentamidine is a cationic drug that is used for the treatment of African trypanosomiasis, leishmaniasis, and Pneumocystis carinii pneumonia. When incubated with pharmacological concentrations of pentamidine, some of the etiologic agents of those diseases reach internal concentrations close to 1.0 mM. In this work pentamidine is shown to exhibit characteristics of a cationic uncoupler of oxidative phosphorylation in isolated rat liver mitochondria: it released respiratory control, enhanced the latent ATPase activity, and released the inhibition of State 3 respiration by oligomycin. Maximal stimulation of respiration and ATPase activity was observed at a concentration of pentamidine of 200-300 microM. Higher concentrations had an inhibitory effect on mitochondrial respiration. As it happens with other cationic uncouplers, the uncoupling effect of pentamidine required inorganic phosphate. Pentamidine-induced uncoupling of oxidative phosphorylation was accompanied by an efflux of Ca2+ from the mitochondria and partial collapse of the mitochondrial membrane potential.

Animals↗
PubMed1997

Effects of organophosphorous compounds on fatty acid compositions and oxidative phosphorylation system in the brain of rats.

Effects of organophosphorous compounds, O,O-dimethyl O-4-nitro-m-tolyl phosphorothioate (MEP), O-ethyl O-p-nitrophenyl phenylphosphonothioate (EPN) and O-(4-cyanophenyl) O-ethyl phenylphosphonothioate (CYP), on the fatty acid composition and the subsequent effects on the oxidative phosphorylation system in the brain of rats were studied. After 6 days exposure in pesticides, polyunsaturated fatty acids in brain free fatty acid fractions of CYP treated rats decreased, and the unsaturation index in them were lower than those in the control rats. The polyunsaturated/saturated ratio (P/S ratio) in brain total lipids of CYP treated rats was lower than that in the control. The fatty acid composition in the brain of EPN treated rats had the same inclination as that of CYP treated rats. In the P/S ratio and unsaturation index in serum no difference was observed between CYP treated rats and the control, therefore CYP could affect the fatty acid composition in the rat brain directly. Free fatty acid contents in the brain of EPN and CYP treated rats decreased after 6 days exposure. Activities of complex I of brains were significantly higher in the EPN and CYP exposed rats than in the control rats in spite of the fact that no difference of ATP productivity was observed between them. These results suggest that EPN and CYP may affect the free fatty acid content, especially the polyunsaturated fatty acid content and consequently the enzyme activities in the oxidative phosphorylation system in the brain. Those phenomena, however, were not observed after 28 days exposure in pesticide, therefore those effects may be a passing phenomenon in an acute stage.

Animals↗