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PubMed2005

Functional coupling between nucleoside diphosphate kinase of the outer mitochondrial compartment and oxidative phosphorylation.

In rat liver mitochondria all nucleoside diphosphate kinase of the outer compartment is associated with the outer surface of the outer membrane (Lipskaya, T. Yu., and Plakida, K. N. (2003) Biochemistry (Moscow), 68, 1136-1144). In the present study, three systems operating as ADP donors for oxidative phosphorylation have been investigated. The outer membrane bound nucleoside diphosphate kinase was the first system tested. Two others employed yeast hexokinase and yeast nucleoside diphosphate kinase. The two enzymes exhibited the same activity but could not bind to mitochondrial membranes. In all three systems, muscle creatine phosphokinase was the external agent competing with the oxidative phosphorylation system for ADP. Determination of mitochondrial respiration rate in the presence of increasing quantities of creatine phosphokinase revealed that at large excess of creatine phosphokinase activity over other kinase activities (of the three systems tested) and oxidative phosphorylation the creatine phosphokinase reaction reached a quasi-equilibrium state. Under these conditions equilibrium concentrations of all creatine phosphokinase substrates were determined and K(eq)app of this reaction was calculated for the system with yeast hexokinase. In samples containing active mitochondrial nucleoside diphosphate kinase the concentrations of ATP, creatine, and phosphocreatine were determined and the quasi-equilibrium concentration of ADP was calculated using the K(eq)app value. At balance of quasi-equilibrium concentrations of ADP and ATP/ADP ratio the mitochondrial respiration rate in the system containing nucleoside diphosphate kinase was 21% of the respiration rate assayed in the absence of creatine phosphokinase; in the system containing yeast hexokinase this parameter was only 7% of the respiration rate assayed in the absence of creatine phosphokinase. Substitution of mitochondrial nucleoside diphosphate kinase with yeast nucleoside diphosphate kinase abolished this difference. It is concluded that oxidative phosphorylation is accompanied by appearance of functional coupling between mitochondrial nucleoside diphosphate kinase and the oxidative phosphorylation system. Possible mechanisms of this coupling are discussed.

Adenosine Diphosphate↗
PubMed1985

Regulation of the degree of coupling of oxidative phosphorylation in intact rat liver.

The degree of coupling of oxidative phopshorylation q was determined in isolated perfused livers and in livers in vivo from fed and fasted rats. This determination of q was based on a simple nonequilibrium-thermodynamic representation of the major reactions of cytosolic adenine nucleotides, and made use of the measured cytosolic concentrations of adenine nucleotides, phosphate, and lactate/pyruvate ratios in extracted livers. The deviations of the measured values from the theoretically predicted ones at different mass action ratios of the adenylate kinase reaction showed that the basic assumptions of the model, including linearity between flows and thermodynamic forces, were fulfilled in intact liver within the experimental error. The degree of coupling was higher in livers from fed rats than in livers from fasted rats. In particular, the determined values of q were close to the theoretical degrees of coupling qecp and qecf which allow maximization of output power and output flow of oxidative phosphorylation for fed and fasted states, respectively, at optimal efficiency and minimal energy costs. This finding indicates that conductance matching between the load and phosphorylation is fulfilled in vivo. Moreover, it was found that fatty acids lower the degree of coupling in a concentration-dependent manner. This suggested that in livers in the fasted state q is decreased due to elevated fatty-acid levels. Thus fatty acids could act as metabolic regulators of the degree of coupling, enabling the cell to optimize efficiency of oxidative phosphorylation under different metabolic regimes.

Adenine Nucleotides↗
PubMed1997

Rapid isolation of muscle and heart mitochondria, the lability of oxidative phosphorylation and attempts to stabilize the process in vitro by taurine, carnitine and other compounds.

We modified the isolation procedure of muscle and heart mitochondria. In human muscle, this resulted in a 3.4 fold higher yield of better coupled mitochondria in half the isolation time. In a preparation from rat muscle we studied factors that affected the stability of oxidative phosphorylation (oxphos) and found that it decreased by shaking the preparation on a Vortex machine, by exposure to light and by an increase in storage temperature. The decay was found to be different for each substrate tested. The oxidation of ascorbate was most stable and less sensitive to the treatments. When mitochondria were stored in the dark and the cold, the decrease in oxidative phosphorylation followed first order kinetics. In individual preparations of muscle and heart mitochondria, protection of oxidative phosphorylation was found by adding candidate stabilizers, such as desferrioxamine, lazaroids, taurine, carnitine, phosphocreatine, N-acetylcysteine. Trolox-C and ruthenium red, implying a role for reactive oxygen species and calcium-ions in the in vitro damage at low temperature to oxidative phosphorylation. In heart mitochondria oxphos with pyruvate and palmitoylcarnitine was most labile followed by glutamate, succinate and ascorbate. We studied the effect of taurine, hypotaurine, carnitine, and desferrioxamine on the decay of oxphos with these substrates. 1 mM taurine (n = 6) caused a significant protection of oxphos with pyruvate, glutamate and palmitoylcarnitine, but not with the other substrates. 5 mM L-carnitine (n = 6), 1 mM hypotaurine (n = 3) and 0.1 mM desferrioxamine (n = 3) did not protect oxphos with any of the substrates at a significant level. These experiments were undertaken in the hope that the in vitro stabilizers can be used in future treatment of patients with defects in oxidative phosphorylation.

Animals↗
PubMed2003

Training-induced adaptation of oxidative phosphorylation in skeletal muscles.

Muscle training/conditioning improves the adaptation of oxidative phosphorylation in skeletal muscles to physical exercise. However, the mechanisms underlying this adaptation are still not understood fully. By quantitative analysis of the existing experimental results, we show that training-induced acceleration of oxygen-uptake kinetics at the onset of exercise and improvement of ATP/ADP stability due to physical training are mainly caused by an increase in the amount of mitochondrial proteins and by an intensification of the parallel activation of ATP usage and ATP supply (increase in direct stimulation of oxidative phosphorylation complexes accompanying stimulation of ATP consumption) during exercise.

Adaptation, Physiological↗
PubMed2004

Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage.

In Alzheimer's disease (AD) pathogenesis, increasing evidence implicates mitochondrial dysfunction resulting from molecular defects in oxidative phosphorylation (OXPHOS). The objective of the present study was to determine the role of mRNA expression of mitochondrial genes responsible for OXPHOS in brain specimens from early AD and definite AD patients. In the present article, using quantitative real-time polymerase chain reaction (PCR) techniques, we studied mRNA expression of 11 mitochondrial-encoded genes in early AD patients (n = 6), definite AD patients (n = 6), and control subjects (n = 6). Using immunofluorescence techniques, we determined differentially expressed mitochondrial genes NADH 15-kDa subunit (complex I), cytochrome oxidase subunit 1 (complex IV), and ATPase delta-subunit (complex V) in the brain sections of AD patients and control subjects. Our quantitative reverse transcription (RT)-PCR analysis revealed a downregulation of mitochondrial genes in complex I of OXPHOS in both early and definite AD brain specimens. Further, the decrease of mRNA fold changes was higher for subunit 1 compared to all other subunits studied, suggesting that subunit 1 is critical for OXPHOS. Contrary to the downregulation of genes in complex I, complexes III and IV showed increased mRNA expressions in the brain specimens of both early and definite AD patients, suggesting a great demand on energy production. Further, mitochondrial gene expression varied greatly across AD patients, suggesting that mitochondrial DNA defects may be responsible for the heterogeneity of the phenotype in AD patients. Our immunofluorescence analyses of cytochrome oxidase and of the ATPase delta-subunit suggest that only subpopulations of neurons are differentially expressed in AD brains. Our double-labeling immunofluorescence analyses of 8-hydroxyguanosine and of cytochrome oxidase suggest that only selective, overexpressed neurons with cytochrome oxidase undergo oxidative damage in AD brains. Based on these results, we propose that an increase in cytochrome oxidase gene expression might be the result of functional compensation by the surviving neurons or an early mitochondrial alteration related to increased oxidative damage.

Aged↗
PubMed1984

Oxidative phosphorylation and the Pi-ATP exchange reaction of submitochondrial particles under the influence of organic solvents.

The effect of some organic solvents, in particular dimethyl sulfoxide, on oxidative phosphorylation, the Pi-ATP exchange reaction, and ATP hydrolysis has been studied in submitochondrial particles from bovine heart. The three reactions are inhibited by dimethyl sulfoxide, but with a different sensitivity. Oxidative phosphorylation takes place at considerable rates in the presence of concentrations of dimethyl sulfoxide that completely inhibit the Pi-ATP exchange reaction. The sensitivity of the Pi-ITP exchange reaction to dimethyl sulfoxide measured in the presence of electron transport is also higher than that of oxidative phosphorylation. Dimethyl sulfoxide inhibits an electrochemical H+ gradient-dependent stimulating effect of inorganic phosphate on ATP hydrolysis which is linked to the Pi-ATP exchange reaction. In the absence of phosphate or in the presence of phosphate plus uncoupler, dimethyl sulfoxide does not inhibit hydrolysis. These findings, together with the observation that electron transport increases the rate of the Pi-ITP exchange reaction, suggest that electrochemical H+ gradients modify the kinetic characteristics of particulate Fi-ATPase. Glycerol and methanol, but not dimethylformamide, induce effects similar to those of dimethyl sulfoxide on oxidative phosphorylation and the Pi-ATP exchange reaction. This suggests that the described effects of solvents could be due to alterations of water structure.

Adenosine Triphosphate↗
PubMed1972

Mechanisms of pathogenesis in Listeria monocytogenes infection. VI. Oxidative phosphorylation in mouse liver mitochondria during experimental listeriosis.

Previous reports have demonstrated early changes in hepatic carbohydrate and energy metabolism in mice infected with Listeria monocytogenes. This study was undertaken to further elucidate mechanisms of damage involved in these changes. Female CD-1 mice were injected intraperitoneally with 10(6)L. monocytogenes A4413. At 0, 10, and 20 hr after infection, groups of mice were sacrificed and the livers were removed and pooled. Oxidative phosphorylation was assayed immediately upon isolation of mitochondria from pooled liver homogenates. Appropriate metabolic inhibitors were employed to examine each of the three phosphorylation sites in mitochondrial electron transport. When pyruvate-malate (equimolar concentrations) and alpha-ketoglutarate were used as substrates, decreases in both phosphorylation and oxidation were noted as early as 10 hr after infection. With beta-hydroxybutyrate and citrate as substrates, alterations were not noted until 20 hr after infection, whereas no changes were seen when glutamate, succinate, or ascorbate were employed. These results suggest possible derangement of the first site in oxidative phosphorylation as well as lowered activity of nicotinamide adenine dinucleotide-linked dehydrogenases during experimental listeriosis in mice.

Animals↗
PubMed1979

The effect of dianabol on certain cell energy processes in postirradiation disease. III. The effect of chronic administration of dianabol and irradiation on oxidative phosphorylation in rat liver mitochondria.

Chronic administration of Dianabol did not prevent the radiation-induced changes of oxidative phosphorylation in rat liver mitochondria. Irradiation of rats with X-rays, in a dose of 600 R for the whole body, causes damage of oxidative phosphorylation in rat liver mitochondria. Progressive reducation of oxygen consumption, decrease of high-energy bond formation and a drop of the P/O coefficient were observed in irradiated animals. The presumable role of the postirradiation damage of oxidative phosphorylation and the effects of radioprotective compounds on this process are discussed.

Animals↗
PubMed1985

Action of bepridil, a new calcium channel blocker on oxidative phosphorylation, oligomycin-sensitive adenosine triphosphatase activity, swelling, Ca++ uptake and Na+-induced Ca++ release processes of rabbit heart mitochondria in vitro.

Effects of bepridil [1-[3-isobutoxy-2]benzylphenyl-amino)propyl pyrrolidine) on oxidative phosphorylation, oligomycin-sensitive adenosine triphosphatase, swelling, Ca++ uptake and Na+-induced Ca++ release processes of mitochondria isolated from rabbit heart were investigated. Bepridil, in concentrations greater than 5 microM, produced uncoupling of oxidative phosphorylation and stimulated oligomycin-sensitive adenosine triphosphatase activity. At low concentrations it prevented inorganic phosphate-induced swelling and associated depression of oxidative phosphorylation. Its effectiveness in preventing swelling and depression of oxidative phosphorylation was found to be dependent on inorganic phosphate concentration. A concentration of 1 microM of bepridil was effective in producing 50% less depression of phosphorylating respiration in the presence of 10 mM inorganic phosphate. Concentrations of bepridil above 25 microM inhibited the rate of Ca++ uptake. A 50% inhibition of Ca++ uptake was observed at 93 microM bepridil. The rate of Na+-induced Ca++ release was also inhibited by bepridil. A 50% inhibition of the rate of Na+-induced Ca++ release occurred at 11 microM of bepridil. When the Na+-dependent Ca++ release process was about 80% inhibited by 25 microM bepridil, the uptake process still remained at the same level as the untreated control. Results suggest that in addition to reported effects on sarcolemma and sarcoplasmic reticulum, mitochondria are also affected by bepridil.

Adenosine Triphosphatases↗
PubMed1994

Mechanistic stoichiometry of yeast mitochondrial oxidative phosphorylation.

This study investigates the relationships between the efficiency of oxidative phosphorylation (ATP/O) and respiratory flux in yeast mitochondria. To manipulate the electron flux through the respiratory chain, different substrates leading to NAD(P)H were used. By testing the effect of ADP either on respiratory rate in the presence or absence of oligomycin or on the level of NAD(P)H, on one hand, and the effects of uncouplers on respiration, on the other, we distinguished several categories of substrates: those for which the low respiration rate was mainly controlled by dehydrogenase activities and others for which the respiration was high and controlled downstream from the dehydrogenases. By using these different substrates, we observed that the ATP/O ratio decreased irrespective of the proton-motive force when the electron flux increased, unlike the situation when the respiratory rate was modulated by addition of the respiratory inhibitor. This result suggests that the oxidative phosphorylation efficiency depends on the value of the flux crossing the proton pumps. This relationship between efficiency (ATP/O) and electron flux was linked to a main control upstream from the respiratory chain. Such changes in the ATP/O ratio at least involved changes in the stoichiometry (H+/2e-) of the respiratory chain. Indeed, in non-phosphorylating mitochondria, the ratio of stoichiometries at site 2+3 over site 3 varied according to the proton-motive force. This cannot be explained by a variation in proton leak alone but involved both (i) a variable stoichiometry (H+/2e-) in relation to the electron flux value and (ii) different relationships between the variation in stoichiometry and the flux value at each coupling site.

Adenosine Triphosphate↗
PubMed1987

Regulation of oxidative phosphorylation in mitochondria of epididymal bull spermatozoa.

The regulation of oxidative phosphorylation was studied with digitonin-treated epididymal bull spermatozoa in which mitochondria are directly accessible to low molecular compounds in the extracellular medium. Due to the high extramitochondrial ATPase activity in this cell preparation, it was possible to stimulate respiration to a small extent only by added hexokinase in the presence of glucose and adenine nucleotides. Added pyruvate kinase plus phosphoenol pyruvate, however, strongly suppressed the respiration. Under these conditions, the respiration was found to depend on the extramitochondrial [ATP]/[ADP] ratio in the range of 1-100. The contribution of the adenine nucleotide translocator to this dependence was determined by titration with the irreversible inhibitor carboxyatractyloside in the presence of ADP. Using lactate plus malate as substrate, the active state respiration was controlled to about 30% by the translocator, whereas 12 and 4% were determined in the presence of L-glycerol-3-phosphate and malate alone, respectively. In order to compare the results with those for intact cells, the adenine nucleotide patterns were determined in intact and digitonin-treated spermatozoa under conditions of controlled respiration in the presence of vanadate and carboxyatractyloside, respectively. About 21% of total cellular adenine nucleotides were found in digitonin-treated cells representing the mitochondrial compartment. While allowing for the intramitochondrial amount of adenine nucleotides, the cytosolic [ATP]/[ADP] ratio was estimated to be 6-times higher than the mitochondrial ratio in intact cells. It is concluded from the data presented that the principal mechanism by which oxidative phosphorylation in sperm mitochondria is regulated via the extramitochondrial [ATP]/[ADP] ratio is the same as that demonstrated for other isolated mitochondria.

Adenine Nucleotides↗
PubMed1986

Effect of the bacterial DNA gyrase inhibitors, novobiocin, nalidixic acid, and oxolinic acid, on oxidative phosphorylation.

When incubated with isolated intact rat liver mitochondria, novobiocin and nalidixic acid act as uncouplers of oxidative phosphorylation; they stimulate oxygen uptake and inhibit ATP synthesis. Novobiocin is about as powerful an uncoupler as is 2,4-dinitrophenol, nalidixic acid is somewhat less powerful, and oxolinic acid exerts no inhibition whatsoever at the concentrations used. The three inhibitors are without effect on oxidative phosphorylation in Escherichia coli nor does novobiocin affect this process in a novobiocin-permeable mutant of yeast. While it would appear that oxolinic acid may be a relatively specific tool for the manipulation of the superhelicity of DNA in complex systems such as mammalian mitochondria and intact mammalian cells, the specificity of each of these inhibitors may depend upon the particular conditions and species used and such experiments require adequate controls on oxidative phosphorylation.

Animals↗
PubMed1986

Respiratory and oxidative phosphorylation of myocardial mitochondria in hypertrophied and failing hearts.

Respiratory and oxidative phosphorylation activity of mitochondria was studied in the course of the adaptation of the heart to haemodynamic overload in rabbit due to aortic valve insufficiency. In the period of developing cardiac hypertrophy, the rate of oxygen consumption in stage 3, i.e. in the stage of ATP formation, and the phosphorylation rate significantly increase. In the period of regression of cardiac hypertrophy, which precedes heart failure, the respiratory and oxidative phosphorylation activity does not significantly change. In a failing heart, the respiratory rate in stage 3 returns to normal and the phosphorylation rate increases in comparison with normal rabbits. The results of the study show that in the myocardium of hypertrophied non-failing as well as failing heart after prolonged haemodynamic overload, the primary function of mitochondria, i.e. energy production is sufficiently preserved.

Adenosine Triphosphate↗
PubMed1983

Reserpine as an uncoupler of oxidative phosphorylation and the relevance to its psychoactive properties.

Many drugs differing widely in chemical structure uncouple mitochondrial oxidative phosphorylation in vitro. This observation has led to the hypothesis that in vivo uncoupling is the basis of their pharmacological activity. Serpasil, a parenteral preparation of reserpine, recently has been shown to uncouple oxidative phosphorylation in vervet monkey kidney mitochondria. Although the drug exhibits some properties of a "classical" uncoupler, our studies show that it has a dual effect on energy conservation. Reserpine released respiratory control in rat liver mitochondria only when dissolved in organic solvents (as in Serpasil) or when deprotonated. Reserpine also released the oligomycin-induced respiratory control in beef heart submitochondrial particles, and inhibited energized uptake of Ca2- by rat liver mitochondria. Reserpine had a dual effect on mitochondrial ATPase: It (a) enhanced ATP hydrolysis by intact liver mitochondria, and (b) inhibited ATP hydrolysis by submitochondrial particles of beef heart. On a molar basis, reserpine was less effective than carbonyl cyanide 3-chlorophenylhydrazone in all bioenergetic reactions examined. Homogenates and mitochondria isolated from brain and liver of rats stuporous from intraperitoneally injections of Serpasil exhibited no detectable abnormalities in respiratory states and responded to known uncouplers in the expected manner. There was no evidence of in vivo uncoupling of oxidative phosphorylation as a basis of the pharmacological activity of reserpine, although interference with energy transfer may be involved in toxic manifestations of the drug. The results indicate the need for caution in interpreting the action of drugs formulated in complex pharmaceutical preparations and based solely on in vitro experiments.

2,4-Dinitrophenol↗
PubMed2003

The use of lymphocytes to screen for oxidative phosphorylation disorders.

Biochemical analysis of oxidative phosphorylation (OXPHOS) disorders is traditionally carried out on muscle biopsies, cultured fibroblasts, and transformed lymphocytes. Here we present a new screening technique using lymphocytes to identify OXPHOS dysfunction and initially avoid an invasive diagnostic procedure. Lymphocytes represent an easily obtainable source of tissue that presents advantages over the use of fibroblasts or lymphoblast cell lines. The time delay in culturing skin fibroblasts and the interactions between cell transformation and mitochondrial activity are avoided in this methodology. The method requires a small amount of blood (<5 mL); can be completed in a few hours, and allows for repeated measurements. Our assay has been adapted from published methods utilizing cultured fibroblasts and transformed lymphocytes, and our data suggest that measurement of ATP synthesis in lymphocytes is an effective screening tool for diagnosing OXPHOS disorders. This method may also provide an objective tool for monitoring response to treatment and evaluating progression of disease.

Adult↗
PubMed1997

The yield of oxidative phosphorylation is controlled both by force and flux.

Dissipation of energy during oxidative phosphorylation may be due to two distinct mechanisms: passive permeability to protons and/or cations (leak) or decrease in the efficiency of some proton pumps (slip). Whatever the mechanism involved, it is admitted that the wastage depends on the protonmotive force. However, the most relevant question in physiology is to determine whether other factors contribute or not to this efficiency. By comparing phosphorylating (high respiratory flux) or non phosphorylating (low respiratory flux) states at similar protonmotive force, we have shown that the wastage is higher in phosphorylating than in non-phosphorylating conditions. This strongly argues for the fact that the flux of oxidative phosphorylation is an important parameter in the control of the yield of this major energetic pathway.

Adenosine Triphosphate↗
PubMed1977

Studies of energy-linked reactions. Inhibition of oxidative phosphorylation by DL-8-methyldihydrolipoate.

1. DL-8-Methyldihydrolipoate was shown to be a potent inhibitor of mitochondrial oxidative phosphorylation and ATP-driven energy-linked reactions. 2. ADP-stimulated respiration utilizing pyruvate + malate and succinate in both ox heart and rat liver mitochondria is inhibited; oxidative phosphorylation using pyruvate + malate, succinate and ascorbate + NNN'N'-tetramethyl-p-phenylenediamine as substrates is also inhibited; uncoupler-stimulated respiration is unaffected regardless of the substrate used. 3. Mitochondrial oligomycin-sensitive adenosine triphosphatase is inhibited in both the membrane-bound form and the purified detergent-dispersed preparation. 4. ATP-driven transhydrogenase and the ATP-driven energy-linked reduction of NAD+ by succinate in ox heart submitochondrial particles are inhibited, whereas the respiratory-chain-driven transhydrogenase is unaffected. 5. DL-8-Methyl-lipoate has no immediate effect on the above reactions, demonstrating the requirement for the reduced form for inhibition. 6. The inhibitory properties of DL-8-methyldihydrolipoate are analogous to those of oligomycin and provide further evidence of a role for lipoic acid in oxidative phosphorylation.

Adenosine Triphosphatases↗