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PubMed2000

Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-x(L) in osteosarcoma cells.

We explored the role of low mitochondrial membrane potential (DeltaPsim) and the lack of oxidative phosphorylation in apoptosis by assessing the susceptibility of osteosarcoma cell lines with and without mitochondrial DNA to staurosporine-induced death. Our cells without mitochondrial DNA had low DeltaPsim and no functional oxidative phosphorylation. Contrary to our expectation, these cells were more resistant to staurosporine-induced death than were the parental cells. This reduced susceptibility was associated with decreased activation of caspase 3 but not with the mitochondrial permeability transition pore or cytochrome c release from the mitochondria. Apoptosis in both cell lines was associated with an increase in DeltaPsim. Bcl-x(L) could protect both cell types against caspase 3 activation and apoptosis by a mechanism that does not appear to be mediated by mitochondrial function or modulation of DeltaPsim. Nevertheless, we found that Bcl-x(L) expression can stimulate cell respiration in cells with mitochondrial DNA. Our results showed that the lack of functional oxidative phosphorylation and/or low mitochondrial membrane potential are associated with an antiapoptotic effect, possibly contributing to the development of some types of cancer. It also reinforces a model in which Bcl-x(L) can exert an antiapoptotic effect by stimulating oxidative phosphorylation and/or inhibiting caspase activation.

Adenosine Triphosphate↗

PubMed1996

Effect of GLUT1 glucose transporter overexpression on the stimulation of glucose transport in response to inhibition of oxidative phosphorylation.

Glucose transport is markedly stimulated in response to inhibition of oxidative phosphorylation by cyanide or azide in Clone 9 cells, a rat liver cell line in which only the GLUT1 isoform of glucose transporters is expressed. Here, we examine the possibility that the stimulation of glucose transport by azide is similarly observed in cells exhibiting high basal rates of glucose transport. We stably transfected Clone 9 cells with an expression plasmid containing full-length rat GLUT1 cDNA; nontransfected cells and cells transfected with plasmid alone served as controls. Two clones of cells transfected with the GLUT1-cDNA-containing insert, labeled A and B, respectively, expressed 8- and 20-fold higher levels of GLUT1 mRNA, contained 11- and 23-fold higher levels of GLUT1, and manifested 11- and 17-fold higher rates of glucose transport in the basal state. Upon incubation with 5 mM azide for 2 h, the rate of glucose transport was markedly stimulated in both clones. Moreover, the transient fall in cell ATP content following exposure to azide did not correlate with the magnitude of the glucose transport response. We conclude that in GLUT1-overexpressing Clone 9 cells (i) GLUT1 content and glucose transport parallel cellular GLUT1 mRNA content, suggesting no major translational or posttranslational control of GLUT1 expression and function in the basal state, and (ii) the rate of glucose transport in cells overexpressing GLUT1 is markedly stimulated by exposure to azide. These results indicate that the stimulation of glucose transport in response to inhibition of oxidative phosphorylation is maintained in cells with very high basal rates of glucose transport.

Adenosine Triphosphate↗

PubMed1993

Control of oxidative phosphorylation in rat muscle mitochondria: implications for mitochondrial myopathies.

The control of oxidative phosphorylation has been studied in normal skeletal muscle isolated from the hind legs of rats. The control coefficients of different steps of oxidative phosphorylation on the flux of O2 consumption were determined by the inhibitor method and calculation was done according to the model of Gellerich et al. (FEBS Lett. 274 (1990) 167-170) using a non-linear regression fitting procedure. The respiration was recorded with pyruvate (+malate) and palmitoyl-L-carnitine (+malate) as respiratory substrates, which are the main substrates oxidized in the muscle. It appears that the control is broadly distributed among the different complexes of the respiratory chain, and of the ATP synthesis system. Our results also provide an explanation for the threshold effects often evidenced in the clinical manifestation of mitochondrial diseases.

Animals↗

PubMed1997

Postischemic administration of succinate reverses the impairment of oxidative phosphorylation after cardiac ischemia and reperfusion injury.

BACKGROUND: Ischemia and reperfusion (IR) can lead to impaired myocardial mechanical function and inhibition of key metabolic enzyme systems after IR. In this study, we sought to identify the postischemic lesion in oxidative phosphorylation and hypothesized that selective substrate repletion would restore mitochondrial metabolic function during reperfusion. METHODS AND RESULTS: Isolated rat hearts were subjected to global ischemia (25 minutes; 37 degrees C) and reperfusion (40 minutes). Left ventricular developed pressure (LVDP) and the cytochrome a,a3 redox state (near infrared spectroscopy) were continuously monitored. Oxygen consumption was measured for the NADH (mitochondrial complex I) and FADH2 (complex II) pathways in both the resting and maximal ADP-stimulated states. Myocellular oxidative phosphorylation capacity was measured using an NADPH-linked assay specific for mitochondrial ATPase. The hearts were randomized to either succinate (200 micromol/L) or control for the first 5 minutes of reperfusion after ischemia. IR in the control group resulted in an impairment of NADH (complex I) oxidative phosphorylation capacity (1.4+/-0.4 versus control 3.9+/-0.6 nmol ATP/min/mg) and depressed LVDP (49+/-3% of baseline; P<.05). The oxidative phosphorylation capacity for the succinate-using FADH2 pathway remained intact (2.6+/-0.3 versus 2.4+/-0.4). Postischemic succinate administration enhanced LVDP recovery after IR (89+/-8% of baseline; P<.05). Diminished electron transport resulted in depletion of electrons from cytochrome a,a3 during ischemia and early reperfusion, which was reversed by providing succinate as substrate. CONCLUSIONS: Cardiac ischemia and reperfusion results in a defect at mitochondrial complex I but not complex II. Cytochrome a,a3 undergoes anomalous oxidation during ischemia. Postischemic administration of succinate infusion restores the cytochrome a,a3 redox state balance and myocardial function after IR.

Adenosine Triphosphate↗

PubMed1994

Caffeine and Ca2+ stimulate mitochondrial oxidative phosphorylation in saponin-skinned human skeletal muscle fibers due to activation of actomyosin ATPase.

The rate of mitochondrial oxidative phosphorylation of saponin-skinned human muscle fibers from m. vastus lateralis in the presence of glutamate, malate and ATP is reported to be sensitive to caffeine and to changes of free calcium ion concentration. An approximately twofold increase in respiration was observed by the addition of 15 mM caffeine, because of the efflux of calcium from sarcoplasmic reticulum. Direct addition of a Ca2+/CaEGTA buffer, containing 1.5 microM free calcium ions had a similar effect. The ATP-splitting activity of skinned fibers was also stimulated by caffeine or calcium. These observations can be explained exclusively by the calcium-induced activation of actomyosin ATPase. (i) Thapsigargin, an inhibitor of the sarcoplasmic reticulum Ca(2+)-ATPase, had no influence. (ii) In myosin-extracted 'ghost' fibers containing intact mitochondria and an intact sarcoplasmic reticulum caffeine had a negligible effect on oxidative phosphorylation. (iii) The caffeine-induced increase in rate of fiber respiration was concomitant with a decrease in mitochondrial membrane potential and a decrease in the redox state of the mitochondrial NAD system. (iv) The calcium ionophore A 23187 caused a stimulation of respiration and ATP-splitting activity, similar to caffeine. (v) The calcium dependencies of respiration and ATP splitting activity of saponin-skinned human muscle fibers were in experimental error identical. Therefore it is concluded that calcium efflux from sarcoplasmic reticulum affects oxidative phosphorylation in skeletal muscle mostly via the stimulation of actomyosin ATPase.

Caffeine↗

PubMed1993

Interactions between glucose metabolism and oxidative phosphorylations on respiratory-competent Saccharomyces cerevisiae cells.

The purpose of this work was to analyze the interactions between oxidative phosphorylations and glucose metabolism on yeast cells aerobically grown on lactate as carbon source and incubated in a resting cell medium. On such respiratory-competent yeast cells, four different metabolic steady states have particularly been studied: (a) glucose feeding under anaerobiosis, (b) ethanol supply under aerobiosis, (c) glucose supply under aerobiosis and (d) glucose plus ethanol under aerobiosis. For each condition, we measured: (a) the cellular ATP/ADP ratio and NADH content sustained under these conditions, (b) the glucose consumption rate (glucose conditions) and the respiratory rate (aerobic conditions). Under aerobic conditions, when ethanol is used as substrate, the ATP/ADP ratio and NADH level are very high as compared with glucose feeding. However, the rate of oxygen consumption is similar under both conditions. The main observation is a large increase in the respiratory rate when both glucose and ethanol are added. This increase corresponds to an ATP/ADP ratio and a NADH level lower than those observed with ethanol but higher than those with glucose. Therefore the response of the respiratory rate to the ATP/ADP ratio depends on the redox potential. We studied the way in which the ATP-consuming activity was increased under glucose+ethanol conditions. By NMR experiments, it appears that neither the futile cycle at the level of the phosphofructo-1-kinase/fructo-1,6-bisphosphatase couple nor the synthesis of carbohydrate stores could account for the increase in oxidative phosphorylation. However, it is shown that, in the presence of glucose+ethanol, ATP consumption is strongly stimulated. It is hypothesized that this consumption is essentially due to the combination of the well-known plasma membrane proton-ATPase activation by glucose and the high phosphate potential due to oxidative ethanol metabolism. While it is well documented that oxidative phosphorylations inhibit the glycolytic flux, i.e. the Pasteur effect, we clearly show in this work that the glycolytic pathway limits the ability of mitochondria to maintain a cellular phosphate potential.

Adenosine Diphosphate↗

PubMed1988

Redistribution of the flux-control coefficients in mitochondrial oxidative phosphorylations in the course of brain edema.

This work describes the control exerted by dicarboxylate carrier and succinate dehydrogenase activities on the oxidative phosphorylations in rabbit brain mitochondria as an edema develops. Vasogenic edema leads to an uncompetitive inhibition of succinate dehydrogenase activity and to a large decrease of oxidative phosphorylations linked to succinate utilisation. Naftidrofuryl treatment in vivo restores both a high succinate dehydrogenase activity and a normal respiratory rate. In order to quantify the control of oxidative phosphorylations by the succinate dehydrogenase step, we applied the control analysis (Kacser, H. and Burns, J.A. (1973) in Rate Control of Biological Processes (Davies, D.D., ed.), pp. 65-104, Cambridge University Press, London; Heinrich, R. and Rapoport, T.A. (1974) Eur. J. Biochem. 42, 89-95). By using two inhibitors, one (phenylsuccinate) acting only on the dicarboxylate carrier and another (malonate) acting on both the dicarboxylate carrier and the succinate dehydrogenase, a method was developed to calculate the control coefficients of these two steps. The main result is that in mitochondria isolated from normal tissue succinate dehydrogenase exerted no control, but in the course of edema this enzymatic step became a controlling one: a transition from zero to a high control coefficient (0.5) was observed from the onset of intracellular edema for the threshold value of water/dry-weight tissue of 4.6.

Animals↗

PubMed1976

[The effect of uncouplers of oxidative phosphorylation on granule precipitation of neutral red in normal and tumor cells].

A study of the effect of uncouplers of the oxidative phosphorylation on the interaction on neutral red with the normal mouse fibroblast and tumour L-cells showed the former to retain the capacity for the dye granule formation in the presence of 1x10 4 M 2,4-dinitrophenol (DNP). Another uncoupler of the oxidative phosphorylation - n-trifluoromethoxycarbonycyanidephenylhydrazone (FCCP) depressed the granule formation both in the tumour L-cells and in the mouse normal fibroblasts. The dye uptake in the normal fibroblasts and in the tumour L-cells was inhibited by both the DNP and the FCCR in the concentration which uncoupled the oxidative phosphorylation.

Animals↗

PubMed1993

Trifluoromethanesulfonamide anthelmintics. Protonophoric uncouplers of oxidative phosphorylation.

A series of trifluoromethanesulfonamides (TFMS) was synthesized and tested for uncoupling activity in rat liver mitochondria. With succinate as the mitochondrial substrate, and the respiratory control index (RCI) as an indicator of their uncoupling ability, we found that all of the TFMS tested were uncouplers of oxidative phosphorylation; the effective concentration (RCI I50) ranged from less than 1 microM to greater than 1000 microM. Correlation techniques were used to assess the strength of the relationship between the ability of a TFMS to uncouple oxidative phosphorylation and its ability to lower the electrical resistance of planar bimolecular lipid membranes. There was a highly significant (P < 0.001) positive linear relationship (r = 0.97) between the ability of a TFMS to uncouple oxidative phosphorylation and its ability to lower electrical resistance. These findings are consistent with the view that the TFMS are lipophilic protonophoric uncouplers of mitochondrial oxidative phosphorylation. Quantitative structure-activity relationship studies using experiment and semiempirical molecular orbital theory revealed that the hydrophobicity of a TFMS and its molecular dipole moment were the principal determinants of mitochondrial uncoupling activity within the pKa range examined.

Animals↗

PubMed2005

Uncoupling of oxidative phosphorylation prevents the urinary alcohol level cycling caused by feeding ethanol continuously at a constant rate.

The mechanism of the UAL cycle in the intragastric feeding model of alcoholic liver disease in the rat was investigated by administering dinitrophenol (DNP) with ethanol in the diet. The question was: is the rate of oxidative phosphorylation fluxuation essential for the cycle to occur? The question has been partially answered by showing that rotenone, which inhibits complex I, blocks the cycle by preventing the generation of NAD from NADH. This would inhibit ATP generation from complex I but would not affect oxidative phosphorylation by complex 2 and 3. Since the rate of O2 consumption is normal at the troughs of the cycle and decreases at the peaks of the cycle and the levels of ATP are reduced at the peaks of the cycle, it is likely that the rate of oxidative phosphorylation also cycles. Since 2-4 dinitrophenol (DNP) uncouples oxidative phosphorylation, it was anticipated that feeding it with ethanol would prevent the cycle from occurring. This proved to be the case. In addition, DNP caused energy wasting and prevented the increase in serum alanine aminotranspeptidase caused by ethanol feeding, probably by preventing the hypoxia which occurs at the peaks of the cycle.

2,4-Dinitrophenol↗

PubMed1973

A new concept for energy coupling in oxidative phosphorylation based on a molecular explanation of the oxygen exchange reactions.

The P(i) right arrow over left arrow HOH exchange reaction of oxidative phosphorylation is considerably less sensitive to uncouplers than the P(i) right arrow over left arrow ATP and ATP right arrow over left arrow HOH exchanges. The uncoupler-insensitive P(i) right arrow over left arrow HOH exchange is inhibited by oligomycin. These results and other considerations suggest that the relatively rapid and uncoupler-insensitive P(i) right arrow over left arrow HOH exchange results from a rapid, reversible hydrolysis of a tightly but noncovalently bound ATP at a catalytic site for oxidative phosphorylation, concomitant with interchange of medium and bound P(i). Such tightly bound ATP has been demonstrated in submitochondrial particles in the presence of uncouplers, P(i), and ADP, by rapid labeling from (32)P(i) under essentially steady-state phosphorylation conditions. These results lead to the working hypothesis that in oxidative phosphorylation energy from electron transport causes release of preformed ATP from the catalytic site. This release could logically involve energy-requiring protein conformational change.

Adenosine Diphosphate↗

PubMed1999

Diphenylamine as an important structure of nonsteroidal anti-inflammatory drugs to uncouple mitochondrial oxidative phosphorylation.

A marked difference has been observed in the inhibitory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on oxidative phosphorylation of rat liver mitochondria. It should be noted that some of the potent inhibitors, N-phenylanthranilic acids and diclofenac, have a similar "skeleton" structure, diphenylamine. Diphenylamine itself was found to inhibit oxidative phosphorylation significantly, although its inhibition potency was weaker than that of NSAIDs with a diphenylamine structure. In addition to decreases in the respiration control index (ratio of state 3 to state 4 respiration), these compounds released oligomycin-inhibited state 3 respiration. These results demonstrated that diphenylamine, as well as N-phenylanthranilic acids and diclofenac, was an uncoupler of oxidative phosphorylation of rat liver mitochondria. Thus, diphenylamine was suggested to play an important role in the uncoupling effects of NSAIDs with a diphenylamine skeleton.

Animals↗

PubMed1992

Dietary protein level alters oxidative phosphorylation in heart and liver mitochondria of chicks.

To determine the effects of dietary protein level on cardiac and hepatic mitochondrial oxidative phosphorylation, chicks were fed on semi-purified diets of different protein levels (7, 25, 43 and 61% of metabolizable energy content) for 7, 14 and 21 d. All diets were formulated to contain equivalent fat, mineral and vitamin contents on a gross energy basis. Cardiac and hepatic mitochondrial oxidative phosphorylation rates were assessed polarographically with pyruvate and malate as substrates. Cardiac mitochondria isolated from chicks fed on a 43 or 61% protein-energy diet for 7 d exhibited significantly reduced ADP:oxygen (ADP:O) ratios when compared with mitochondria isolated from chicks fed on a lower-protein-energy diet. Feeding low- (7%) protein-energy diets for 14 d resulted in a relatively increased ADP:O ratio in the heart. Responses of ADP:O ratios to protein level in hepatic mitochondria showed more dependency on protein level than in heart muscle; at all feeding periods the ADP:O ratio decreased with an increase in protein level. As a result, ATP synthesized in the liver, expressed as nmol/mg mitochondrial protein per min, significantly decreased with increased dietary protein level. A parallel correlation was observed, in chicks fed on diets with different levels of protein, between ADP:O ratio for liver mitochondria and body fat. These results suggest that the reduction in oxidative phosphorylation in the heart and liver of animals fed on a higher protein-energy diet may partly contribute to the depression of body fat.

Adenosine Diphosphate↗

PubMed1988

[The role of adenine nucleotide translocator in the regulation of oxidative phosphorylation in heart mitochondria].

The regulatory role of adenine nucleotide translocase in oxidative phosphorylation was determined by titration of respiration of isolated rabbit heart mitochondria with carboxyatractyloside in the creatine phosphokinase ADP-regenerating system, which is not rate-limiting. It was found that the respiration rate is not controlled by adenine nucleotide translocase in states 3 and 4. Within the physiological region of respiration (30-70% of the maximal rate), the control coefficient for ADP/ATP translocase is 0.62-0.75. Thus, translocase plays a key role in the regulation of oxidative phosphorylation.

Animals↗

PubMed1986

Inhibition of oxidative phosphorylation by Ca2+ or Sr2+: a competition with Mg2+ for the formation of adenine nucleotide complexes.

Intramitochondrial Sr2+, similar to Ca2+, inhibits oxidative phosphorylation in intact rat-liver mitochondria. Both Ca2+ and Sr2+ also inhibit the hydrolytic activity of the ATPase in submitochondrial particles. Half-maximal inhibition of ATPase activity was attained at a concentration of 2.5 mM Ca2+ or 5.0 mM Sr2+ when the concentration of Mg2+ in the medium was 1.0 mM. The inhibition of ATPase activity by both cations was strongly decreased by increasing the Mg2+ concentration in the reaction medium. In addition, kinetical data and the determination of the concentration of MgATP, the substrate of the ATPase, in the presence of different concentrations of Ca2+ or Sr2+ strongly indicate that these cations inhibit ATP hydrolysis by competing with Mg2+ for the formation of MgATP. On the basis of a good agreement between these results with submitochondrial particles and the results of titrations of oxidative phosphorylation with carboxyatractyloside or oligomycin in mitochondria loaded with Sr2+ it can be concluded that intramitochondrial Ca2+ or Sr2+ inhibits oxidative phosphorylation in intact mitochondria by decreasing the availability of adenine nucleotides to both the ADP/ATP carrier and the ATP synthase.

Adenine Nucleotides↗

PubMed1991

50 years of biological research--from oxidative phosphorylation to energy requiring transport regulation.

In 1930 adenosine triphosphate appeared in the literature from W. A. Engelhardt's work on avian erythrocytes. This was an early example of oxidative phosphorylation in intact cells, and it required methylene blue and oxygen. Both Belitser and I realized that the use of Warburg manometers for aeration was critical in order to generate oxidative phosphorylation of glucose in tissue preparations. Test tube techniques did not work. In 1956 we were able to describe a human type of diabetes called "galactose diabetes," in which consumption of human or cows' milk provokes mental retardation. Replacement of human or cows' milk products with "vegetable milk" formula in early infancy can prevent retardation. We determined that the disease results from a defect of galactose-one-phosphate uridylyl-transferase, a hereditary enzyme. This type of enzyme defect, if discovered and treated in early infancy, is a benign molecular disease. Regulation of transport systems in mammalian cell cultures are frequently complex energized systems. Perhaps my greatest surprise in this regard was the mere fact that an all-cis "odd" hexose-D-allose turned out to be a highly intense down-regulator of the hexose transport system. Additions of inhibitors of oxidative phosphorylation (such as oligomycin or di-nitrophenol) arrested the allose-mediated down-regulation. We have reason to suspect that the strong down-regulator is a phosphorylated form of D-allose. Thus ends my story about oxidative energized biological phosphorylation systems.

Biochemistry↗

PubMedDate not supplied

[Effect of thymosine on oxidative phosphorylation in mitochondria of mouse liver in the dynamics of chemical carcinogenesis].

Oxidative phosphorylation in the mice liver mitochondria with chemical carcinogenesis was studied as affected by thymosine. It is found that under chemical carcinogenesis the energy metabolism (fraction III) lowered and administration of thymosine in the early periods of carcinogenesis favoured an increase in the indices up to the control level. In the late period of carcinogenesis the mentioned effect was not observed. The favourable effect of thymosine on the oxidative phosphorylation was associated with an increase in the immunological indices in the animals under experiment. It is supposed that the activity of thymosine as a hormonal factor includes participation in the energy metabolism regulation.

Animals↗

PubMed1998

The dynamic regulation of myocardial oxidative phosphorylation: analysis of the response time of oxygen consumption.

Although usually steady-state fluxes and metabolite levels are assessed for the study of metabolic regulation, much can be learned from studying the transient response during quick changes of an input to the system. To this end we study the transient response of O2 consumption in the heart during steps in heart rate. The time course is characterized by the mean response time of O2 consumption which is the first statistical moment of the impulse response function of the system (for mono-exponential responses equal to the time constant). The time course of O2 uptake during quick changes is measured with O2 electrodes in the arterial perfusate and venous effluent of the heart, but the venous signal is delayed with respect to O2 consumption in the mitochondria due to O2 diffusion and vascular transport. We correct for this transport delay by using the mass balance of O2, with all terms (e.g. O2 consumption and vascular O2 transport) taken as function of time. Integration of this mass balance over the duration of the response yields a relation between the mean transit time for O2 and changes in cardiac O2 content. Experimental data on the response times of venous [O2] during step changes in arterial [O2] or in perfusion flow are used to calculate the transport time between mitochondria and the venous O2 electrode. By subtracting the transport time from the response time measured in the venous outflow the mean response time of mitochondrial O2 consumption (tmito) to the step in heart rate is obtained. In isolated rabbit heart we found that tmito to heart rate steps is 4-12 s at 37 degrees C. This means that oxidative phosphorylation responds to changing ATP hydrolysis with some delay, so that the phosphocreatine levels in the heart must be decreased, at least in the early stages after an increase in cardiac ATP hydrolysis. Changes in ADP and inorganic phosphate (Pi) thus play a role in regulating the dynamic adaptation of oxidative phosphorylation, although most steady state NMR measurements in the heart had suggested that ADP and Pi do not change. Indeed, we found with 31P-NMR spectroscopy that phosphocreatine (PCr) and Pi change in the first seconds after a quick change in ATP hydrolysis, but remarkably they do this significantly faster (time constant approximately 2.5 s) than mitochondrial O2 consumption (time constant 12 s). Although it is quite likely that other factors besides ADP and Pi regulate cardiac oxidative phosphorylation, a fascinating alternative explanation is that the first changes in PCr measured with NMR spectroscopy took exclusively place in or near the myofibrils, and that a metabolic wave must then travel with some delay to the mitochondria to stimulate oxidative phosphorylation. The tmito slows with falling temperature, intracellular acidosis, and sometimes also during reperfusion following ischemia and with decreased mitochondrial aerobic capacity. In conclusion, the study of the dynamic adaptation of cardiac oxidative phosphorylation to demand using the mean response time of cardiac mitochondrial O2 consumption is a very valuable tool to investigate the regulation of cardiac mitochondrial energy metabolism in health and disease.

Adenosine Diphosphate↗