[Phosphorylating oxidation: uncoupling at the lever of rat liver mitochondria by Ag 310, reducer of NAD and NADP coenzymes].
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Adenosine Triphosphate↗
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Results for “OXIDATIVE PHOSPHORYLATION”
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[Phosphorylation, oxidation and ubiquinone contents in liver mitochondria of prediabetic and diabetic rats].
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Animals↗
[Characteristics of the "pool" of adenylic nucleotides of a mutant "phosphorylating oxidation" op1 and of the corresponding wild strain].
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Adenine Nucleotides↗
[Oxidative phosphorylation in the intact and regenerating liver from a chronobiological viewpoint].
The dynamics of oxidative phosphorylation of the regenerating liver mitochondria on the endogenous and exogenous (glutamate, succinate, ascorbate) substrates in comparison with the normal diurnal and seasonal changes of this process was studied by the polarographical method. With the increase of its activity reflecting the deviation from the state of physiological rest (intact liver in spring, autumn, winter; regenerating liver), the range and synphasing of the oxidative phosphorylation indices were decreased, their bimodal distributions were transformed into the monomodal ones down to the full loss of diurnal periodicity. The degree of the process desynchronization depends, thus, directly on the degree of its activity.
Animals↗
Uncoupling of rat liver mitochondrial oxidative phosphorylation by the fasciolicide triclabendazole and its sulfoxide and sulfone metabolites.
The uncoupling activity of a narrow-spectrum benzimidazole anthelmintic triclabendazole (TCZ, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylthio-benzimidazole) and its 2 principal metabolites triclabendazole sulfoxide (TCZ sulfoxide, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylsulfinyl-benzimidazole) and triclabendazole sulfone (TCZ sulfone, 6-chloro-5-[2,3-dichlorophenoxyl]-2methylsulfonyl- benzimidazole) has been determined using rat liver mitochondria. With glutamate or succinate as the mitchondrial substrate, and the respiratory control index (RCI) as an indicator of uncoupling activity, we found that TCZ and its 2 main metabolites were uncouplers of oxidative phosphorylation at micromolar concentrations. The rank order of in vitro activity was TCZ sulfone > TCZ sulfoxide > TCZ. Structure-activity relationship studies revealed that the electron-withdrawing power of the substituent in the 2-position was the principal determinant of mitochondrial uncoupling activity. Correlation techniques were used to assess the strength of the relationship between the ability of TCZ and its metabolites to uncouple oxidative phosphorylation and their ability to lower the electrical resistance of planar bimolecular lipid membranes. A log-log plot of RCI I50 vs. resistance effective concentration (REC I50) gave a linear fit with a correlation coefficient (r) of 0.98; an r of 0.98 indicates a high positive relationship between the ability of these fasciolicides to uncouple oxidative phosphorylation and their ability to lower electrical resistance. These findings are consistent with the view that TCZ and its sulfoxide and sulfone metabolites are lipophilic protonophoric uncouplers of rat liver mitochondrial oxidative phosphorylation.
2,4-Dinitrophenol↗
Functioning of oxidative phosphorylation in liver mitochondria of high-fat diet fed rats.
We proposed that inhibition of mitochondrial adenine nucleotide translocator (ANT) by long chain acyl-CoA (LCAC) underlies the mechanism associating obesity and type 2 diabetes. Here we test that after long-term exposure to a high-fat diet (HFD): (i) there is no adaptation of the mitochondrial compartment that would hinder such ANT inhibition, and (ii) ANT has significant control of the relevant aspects of oxidative phosphorylation. After 7 weeks, HFD induced a 24+/-6% increase in hepatic LCAC concentration and accumulation of the oxidative stress marker N(epsilon)-(carboxymethyl)lysine. HFD did not significantly affect mitochondrial copy number, oxygen uptake, membrane potential (Deltapsi), ADP/O ratio, and the content of coenzyme Q(9), cytochromes b and a+a(3). Modular kinetic analysis showed that the kinetics of substrate oxidation, phosphorylation, proton leak, ATP-production and ATP-consumption were not influenced significantly. After HFD-feeding ANT exerted considerable control over oxygen uptake (control coefficient C=0.14) and phosphorylation fluxes (C=0.15), extra- (C=0.23) and intramitochondrial (C=-0.56) ATP/ADP ratios, and Deltapsi (C=-0.11). We conclude that although HFD induces accumulation of LCAC and N(epsilon)-(carboxymethyl)lysine, oxidative phosphorylation does not adapt to these metabolic challenges. Furthermore, ANT retains control of fluxes and intermediates, making inhibition of this enzyme a more probable link between obesity and type 2 diabetes.
Adenine Nucleotide Translocator 3↗
Oxidative phosphorylation in intact chl-r mutants of Escherichia coli K 12.
The efficiency of oxidative phosphorylation was estimated in intact resting cells of Escherichia coli K 12, strain PA 601 (chl-s) and its chl-r mutants, all of them grown anaerobically in the presence of nitrate. The oxidation of endogenous NADH in intact chl-s cells was accompanied by the formation of ATP whatever the terminal electron acceptor, oxygen or nitrate, so that it was possible to conclude that the energy conservation sites are operating with either of the two acceptors in cells grown anaerobically in the presence of nitrate. For chl-r mutants oxidation of endogenous NADH correlated with ATP-production was found only with oxygen as electron acceptor. It is concluded that the energy-conservation sites are preserved in these mutants, the nitrate respiratory chain of which is altered. This assumption is corroborated by the effects of uncouplers of oxidative phosphorylation on ATP-synthesis.
Aerobiosis↗
Some properties of a new phosphorylated derivative of NAD, an intermediate in oxidative phosphorylation.
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Coenzymes↗
[Reasons causing a lag period in the oxidative phosphorylation process. Isn't ATP an internal uncoupler of ATP synthetase?].
The kinetics of oxidative phosphorylation catalyzed by bovine heart submitochondrial particles was studied in a range of MgATP and MgADP concentrations from 0.3 to 10 mM. It is shown that, at a low uncoupler concentration (0.9 microM of tetrachlorotrifluoromethylbenzimidazole, the lag period of the reaction increases from 12 s to 2-3 min, and KM for Pi increases severalfold; the value of Vmax remains practically unchanged. Increasing the [MgATP]/[MgADP] concentration ratio, with their total concentration being unchanged, leads to similar changes in the kinetics of oxidative phosphorylation. The value of delta pH generated on the membrane of AS particles at delta microH+ = 60 delta pH was measured using 9-aminoacridine. It was found that the electrochemical potential of H+ ions shows the same thermodynamic shift in the reaction of energy-dependent Pi -ATP exchange throughout the [MgATP]/[MgADP] concentration range studied, from 0.1 to 10: the synthesis on the ATP molecule is provided by the transmembrane transfer of two H+ ions. It was shown that the binding of ATP and/or ADP in the allosteric site, whose saturation is necessary for the functioning of ATP synthase, occurs with equal constants, 1-2 mM. It is concluded that the lag period in the synthesis of ATP indicates the monomolecular transition ATP hydrolase-->ATP sysnthase, which comes about by the action of transmembrane potential. The binding of MgADP or MgATP renders the enzyme structure "more coupled" or "less coupled", respectively. Structural distinctions manifest themselves in a kinetically different behavior of mitochondrial ATP synthase at [MgATP] > [MgADP] and [MgATP] < [MgADP] and do not suggest futile leakage of H+ through the membrane.
Adenosine Diphosphate↗
Purified hydrophobic proteins, chargerins, are essential for energy transduction in oxidative phosphorylation.
Studies on anisotropic inhibitors, a unique type of inhibitor of energy transduction in oxidative phosphorylation, suggested that redox reactions generate two kinds of negative charges on the outer surface of mitochondrial inner membranes, on redox complexes and on F0, and that the inhibitors inhibit energy transduction by binding to these negative charges. Recent experiments on photoaffinity labeling of mitochondria with monoazide ethidium, which is an anisotropic inhibitor, showed that the inhibitor specifically binds to a hydrophobic protein of the membranes. In the present work the mitochondrial components labeled with monoazide ethidium were further purified and two kinds of hydrophobic proteins (apparent molecular masses, 8 and 13 kDa) were found to be specifically labeled with the inhibitor. These proteins were named chargerin I and II, respectively. Redox reactions greatly increased the molar ratio of ethidium bound to chargerin I and II in mitochondria, reflecting a conformational change of the chargerins coupled with the redox reactions. It was also shown that antibody against chargerin II specifically inhibited ATP synthesis in mitoplasts (inner membranes plus matrix) prepared from rat liver mitochondria. Thus, the present findings show that chargerins have an essential role in energy transduction in oxidative phosphorylation in rat liver mitochondria, in good accord with the conformational coupling model of the H+ pumps and ATP synthesis.
Affinity Labels↗
Role of oxidative phosphorylation in histatin 5-induced cell death in Saccharomyces cerevisiae.
The susceptibility of Saccharomyces cerevisiae to the anti-microbial peptide, histatin 5, was tested after pre-growth in fermentable and non-fermentable carbon sources and in the absence or presence of the uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone (CCCP). S. cerevisiae was more resistant to histatin 5 when grown on a fermentable carbon source compared to growth on a non-fermentable carbon source, indicating an important role for oxidative phosphorylation in histatin 5-induced cell death. Oxidative phosphorylation is a pre-requisite for histatin 5-induced cell death in Candida albicans but this is not the case in S. cerevisiae. Incubation of CCCP-treated S. cerevisiae cells with histatin 5 still resulted in cell death. These results suggest that histatin 5-induced cell death in S. cerevisiae differs from that in C. albicans.
Apoptosis↗
Effects of amiodarone on cardiac function and mitochondrial oxidative phosphorylation during ischemia and reperfusion.
This study was carried out in order to determine if the efficiency of amiodarone, a class III antiarrhythmic agent, is associated with changes in mitochondrial oxidative phosphorylation. A population of 30 rats were treated with amiodarone (100 mg/kg/day) for 5 days. A second population receiving only vehicle was used as control. The hearts were perfused according to the working mode. After 15 min of normoxic perfusion, the left main coronary artery was ligated and the ligation was maintained for 20 min. The ligation was removed and reperfusion continued for a further 30 min. The electrocardiogram was monitored continuously. At the end of perfusion, the ischemic and non ischemic areas were visually separated and mitochondria were harvested from each area. Their oxidative and energy metabolism were assessed with palmitoylcarnitine as substrate in 2 respiration media differing in their free calcium concentration (0 or 0.34 microm). In normoxic conditions, amiodarone treatment increased the cardiac metabolic efficiency (mechanical work to oxygen consumption ratio). The local ischemia decreased the aortic and coronary flows without modifying the cardiac metabolic efficiency. Amiodarone treatment maintained the aortic flow at a significantly higher value; the duration of severe arrhythmias was significantly decreased by the drug. The reperfusion of the ischemic area allowed the partial recovery of fluid dynamics. The coronary flow was restored to 89% of the pre ischemic value. Conversely, the aortic flow never exceeded that measured at the end of ischemia, partly due to the important development of severe arrhythmias. The recovery of aortic flow and metabolic efficiency during reperfusion was improved by amiodarone treatment; ventricular tachycardia and fibrillation duration were reduced. In the mitochondria issued from the normoxic area, the energy metabolism was not altered by the amiodarone treatment, but the presence of calcium in the respiration medium modified the oxidative phosphorylation. The divalent cation slightly decreased the state III respiration rate and increased noticeably the state IV respiration rate. This was associated with an important mitochondrial AMP production and maintenance of ADP in the respiration medium. This energy wasting was reported to decrease the mitochondrial metabolic efficiency. After an ischemia-reperfusion sequence, mitochondrial oxidation phosphorylation was reduced and amiodarone treatment amplified this decrease. This was presumably due to an increased mitochondrial calcium accumulation. Thus, the beneficial properties of amiodarone during reperfusion are supposed to be due to a protection against the deleterious effect of excess matrix calcium on mitochondrial energy metabolism.
Adenine Nucleotides↗
[Effect of hyperbaric oxygenation on the oxidative phosphorylation in mitochondria of normal and ischemic myocardium].
Oxygen, under conditions of elevated pressure 303.975 kPi, was shown to alter oxidative phosphorylation in mitochondria of rabbit heart. Inhibition of oxidative phosphorylation in intact animals and stimulation--in rabbits with myocardial ischemia were observed under conditions of high oxygen pressure. With an increase in frequency of the hyperbaric oxygenation treatments the inhibitory effect if high pressure oxygen was strengthened.
Adenosine Diphosphate↗
Effect of inhibitors of electron transport and oxidative phosphorylation on Trypanosoma cruzi respiration and growth.
Antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide, two specific inhibitors of the b-c1 segment of the respiratory chain, affected the respiration of Trypanosoma cruzi epimastigote forms. The half-maximum inhibitory concentrations were about 0.05 and 4.0 micrograms/mg cells (dry wt.), respectively. The maximum effect of antimycin (about 80% inhibition of respiration) was at about 0.1 microgram antimycin/mg cells. Differential spectrophotometry of T. cruzi epimastigotes in the presence of antimycin, cyanide (or sulfide) and uncouplers, revealed the presence of functional cytochromes aa3, b and c558. In the stationary growth phase respiration by T. cruzi was completely inhibited by cyanide and effectively inhibited by sulfide, but in the exponential growth phase respiration was about 20% insensitive to 5 mM cyanide. Cyanide- and antimycin-insensitive respiration was completely inhibited by salicylhydroxamic acid (2 mM). Antimycin inhibited the operation of the tricarboxylic acids cycle in T. cruzi, as shown by the lesser production of 14CO2 and by the modification of 14C distribution in epimastigotes incubated with [1-14C]glucose, [2-14C]acetate or NaH14CO3. The inhibition of electron transport by antimycin increased the rate of the fumarate reductase reaction, an alternative electron pathway for the oxidation of reduced pyridine nucleotides. Addition of carbonyl cyanide 3-chlorophenylhydrazone to epimastigotes increased the rate of respiration and promoted the oxidation of reduced cytochrome b components, thus showing that these components are subject to respiratory (acceptor) control. Pentachlorophenol similarly affected the cytochrome b redox level but did not modify the rate of respiration. The uncouplers released N,N'-dicyclohexylcarbodiimide inhibition of respiration, and uncouplers and cyanide significantly decreased the ATP level in epimastigotes. The combined effects of the assay inhibitors on respiration, cytochrome b redox level, ATP content and energy charge confirmed the operation of oxidative phosphorylation in T. cruzi epimastigotes. Antimycin, uncouplers and N,N'-dicyclohexylcarbodiimide inhibited growth of T. cruzi, thus proving the essential role of oxidative phosphorylation for the parasite.
Adenosine Triphosphate↗
Significant increase of glycolytic flux in Torulopsis glabrata by inhibition of oxidative phosphorylation.
This study was aimed at increasing the glycolytic flux of the multivitamin-auxotrophic yeast Torulopsis glabrata by disturbing oxidative phosphorylation. We examined two different strategies to impede oxidative phosphorylation. The first strategy was disruption of the activity of the electron transfer chain (ETC), by either of two approaches. One was separately adding, at 10 mg L1, specific inhibitors of complex I (rotenone) or of the bc1 complex (antimycin A) to the culture broth of T. glabrata CCTCC M202019, which resulted in significantly decreased intracellular ATP levels (43% and 27.7%) and significantly increased rates of glucose consumption (qs) and pyruvate production (qp); another approach was breeding a respiratory-deficient mutant RD-16, in which cytochromes aa3 and b in the ETC were deleted after ethidium bromide mutagenesis, to reduce the ETC activity constitutively. The second strategy was inhibiting F0F1-ATP synthase with 0.05 mM oligomycin. Also, a neomycin-resistant mutant with 65% decreased F0F1-ATPase activity was studied. With the two strategies, the specific activity of phosphofructokinase (R2=0.9971), the average specific glucose consumption rate (R2=0.9967) and the average specific pyruvate production rate (R2=0.965) were closely correlated with the intracellular ATP level, all of them being increased at a lower intracellular ATP level.
Adenosine Triphosphate↗
Kinetics and control of oxidative phosphorylation in rat liver mitochondria after dexamethasone treatment.
The present investigation was undertaken in order to evaluate the contributions of ATP synthesis and proton leak reactions to the rate of active respiration of liver mitochondria, which is altered following dexamethasone treatment (1.5 mg/kg per day for 5 days). We applied top-down metabolic control analysis and its extension, elasticity analysis, to gain insight into the mechanisms of glucocorticoid regulation of mitochondrial bioenergetics. Liver mitochondria were isolated from dexamethasone-treated, pair-fed and control rats when in a fed or overnight fasted state. Injection of dexamethasone for 5 days resulted in an increase in the fraction of the proton cycle of phosphorylating liver mitochondria, which was associated with a decrease in the efficiency of the mitochondrial oxidative phosphorylation process in liver. This increase in proton leak activity occurred with little change in the mitochondrial membrane potential, despite a significant decrease in the rate of oxidative phosphorylation. Regulation analysis indicates that mitochondrial membrane potential homoeostasis is achieved by equal inhibition of the mitochondrial substrate oxidation and phosphorylation reactions in rats given dexamethasone. Our results also suggest that active liver mitochondria from dexamethasone-treated rats are capable of maintaining phosphorylation flux for cellular purposes, despite an increase in the energetic cost of mitochondrial ATP production due to increased basal proton permeability of the inner membrane. They also provide a complete description of the effects of dexamethasone treatment on liver mitochondrial bioenergetics.
Adenosine Triphosphate↗
Inhibition of mitochondrial oxidative phosphorylation by adriamycin.
The antitumour antibiotic, adriamycin, inhibited oxidative phosphorylation in freshly prepared mitochondria from the heart, liver and kidney of the rat. It abolished respiratory control and stimulated ATPase activity. Succinate oxidation by heart mitochondria was extremely sensitive to the drug when hexokinase was present in the reaction medium. The sensitive site has been identified to lie in the region between the succinate dehydrogenase flavoprotein and ubiquinone of the respiratory chain.
Adenosine Triphosphatases↗
Role of oxidative phosphorylation and ATP release in mediating birth-related pulmonary vasodilation in fetal lambs.
We investigated the hypothesis that birth-related pulmonary vasodilation is mediated in part by an increase in oxidative phosphorylation and ATP release in response to oxygen exposure at birth. Studies were done in fetal lambs to evaluate the independent effects of oxygen, lung distension alone, or lung distension accompanied by oxygenation and shear stress on fetal pulmonary blood flow and resistance and plasma ATP levels in the pulmonary artery. The effect of each intervention was evaluated in lambs assigned to one of three groups: control or pretreatment with 2,4-dinitrophenol or antimycin-A, inhibitors of oxidative phosphorylation. Exposure to oxygen alone or with lung distension was associated with increases in plasma ATP levels and pulmonary blood flow and a decrease in pulmonary vascular resistance. Plasma ATP levels did not change during lung distension alone. 2,4-Dinitrophenol and antimycin-A attenuated the pulmonary vasodilator response to oxygen but did not attenuate the response to lung distension alone. An increase in oxidative phosphorylation and ATP release during oxygen exposure may contribute to birth-related pulmonary vasodilation in fetal lambs.
Acetylcholine↗