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PubMed2001

A model of oxidative phosphorylation in mammalian skeletal muscle.

A dynamic computer model of oxidative phosphorylation in oxidative mammalian skeletal muscle was developed. The previously published model of oxidative phosphorylation in isolated skeletal muscle mitochondria was extended by incorporation of the creatine kinase system (creatine kinase plus phosphocreatine/creatine pair), cytosolic proton production/consumption system (proton production/consumption by the creatine kinase-catalysed reaction, efflux/influx of protons), physiological size of the adenine nucleotide pool and some additional minor changes. Theoretical studies performed by means of the extended model demonstrated that the CK system, which allows for large changes in P(i) in relation to isolated mitochondria system, has no significant influence on the kinetic properties of oxidative phosphorylation, as inorganic phosphate only slightly modifies the relationship between the respiration rate and [ADP]. Computer simulations also suggested that the second-order dependence of oxidative phosphorylation on [ADP] proposed in the literature refers only to the ATP synthesis flux, but not to the oxygen consumption flux (the difference between these two fluxes being due to the proton leak). Next, time courses of changes in fluxes and metabolite concentrations during transition between different steady-states were simulated. The model suggests, in accordance with previous theoretical predictions, that activation of oxidative phosphorylation by an increase in [ADP] can (roughly) explain the behaviour of the system only at low work intensities, while at higher work intensities parallel activation of different steps of oxidative phosphorylation is involved.

Adenosine Diphosphate↗
PubMed2001

The genetics and pathology of oxidative phosphorylation.

The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway in the production of ATP. The OXPHOS system consists of five multiprotein complexes, the individual subunits of which are encoded either by the mitochondrial or by the nuclear genome. Defects in the OXPHOS system result in devastating, mainly multisystem, diseases, and recent years have seen the description of the underlying genetic mutations in mitochondrial and nuclear genes. Advances in this arena have profited from progress in various genome projects, as well as improvements in our ability to create relevant animal models.

Animals↗
PubMed1990

Uncouplers of oxidative phosphorylation.

Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound.

Acids↗
PubMedDate not supplied

[Lipids as possible proton carriers from the respiratory chain to ATP-synthetase and the mechanism of oxidative phosphorylation].

A scheme of oxidative phosphorylation is suggested according to which at the first stage due to the functioning of the electron-transport chain (ETC) in the points of coupling during relaxation of protein non-equilibrium conformation thermodynamically unfavourable transfer of H+ from H2O into the membrane takes place. Athe 2nd stage H+memb is carried by lipids from ETC-protein to ATP-synthetase. At the 3rd stage ATPase with ATP already contained in the active center seizes 2H+. In the course of subsequent protein relaxation the ATP interaction with the active center is disturbed, and ATP with protons transfers to H2O. In terms of the scheme proposed it proves possible to explain the respiratory control and formation of transmembrane potential difference, as well as the action mechanism of uncouplers and inhibitors of oxidative phosphorylation.

Adenosine Diphosphate↗
PubMed1997

Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation.

Inborn errors of oxidative phosphorylation have been recognized as possible causes of hepatic failure in the neonate, and respiratory enzyme deficiencies have been described in the liver of affected individuals. On the basis of a series of 22 cases, we describe respiratory enzyme deficiency as a cause of early-onset fatal hepatic failure with frequent neurologic involvement. In addition, we have identified a delayed-onset form of hepatic failure with a milder clinical course and inconstant neurologic involvement. Thus we suggest that genetic defects of oxidative phosphorylation be considered as a cause of liver dysfunction in infancy, regardless of the severity of the disease.

Alanine Transaminase↗
PubMed1994

Blastocoel cavity formation by preimplantation rat embryos in the presence of cyanide and other inhibitors of oxidative phosphorylation.

The role of oxidative phosphorylation in blastocoel development in rats was determined by culturing morula stage embryos for 24 h in the presence of three inhibitors of ATP generation: cyanide, antimycin-A and 2,4-dinitrophenol (DNP). Rat morulae could form blastocysts in concentrations of cyanide that are toxic to the embryos of other mammals. Similar results were obtained with antimycin-A and DNP, although DNP reduced the number of blastocysts that formed. A non-invasive ultramicrofluorometric assay was used on single blastocysts and the glycolytic pathway was shown to be stimulated in the presence of these inhibitors. These results suggest that, uniquely among preimplantation embryos studied, the developing rat blastocyst does not have an absolute requirement for oxidative phosphorylation but may be able to compensate by increasing the amount of glucose consumed and metabolized by glycolysis. This pattern of metabolism may be related to the changing maternal environment during development, with blastocoel cavity formation and implantation taking place in increasingly anoxic conditions.

2,4-Dinitrophenol↗
PubMed1980

The optimal efficiency and the economic degrees of coupling of oxidative phosphorylation.

A phenomenological theory considering the output characteristics of oxidative phosphorylation has been worked out by adopting the formalism of linear nonequilibrium thermodynamics. The linearity of oxidative phosphorylation in the range of the output forces of practical interest has been experimentally verified. the efficiency of oxidative phosphorylation is zero if either a load with a zero conductance (open-circuited situation) or a load with an infinite conductance (short-circuited situation) is attached to oxidative phosphorylation. In between these extreme conductances there exists a finite load conductance permitting oxidative phosphorylation to operate with optimal efficiency. The necessary and sufficient condition for optimal efficiency was found to be L33/L11 = square root 1 - q2 where L11 is the phenomenological conductance of phosphorylation, L33 the phenomenological conductance of the load and q the degree of coupling of oxidative phosphorylation driven by respiration. This condition was called conductance matching. Under the condition of conductance matching, four output functions of oxidative phosphorylation of practical interest were optimized. A maximal net rate of oxidative phosphorylation occurs at a degree of coupling qf = 0.78. A maximal output power of oxidative phosphorylation, i.e. net rate times established phosphate potential, resuls at qp = 0.91. The maximization of the function net rate times efficiency yielded an economic degree of coupling qfec = 0.95 for maximal ATP flow. Finally, maximization of the function output power times efficiency led to a degree of coupling qpec = 0.97. This last function simultaneously maximized net rate of ATP production, developed phosphate potential and efficiency and reflects therefore the most economic solution to the output problem under the condition of conductance matching. In isolated rat livers perfused in a metabolic resting state, the condition of conductance matching is fulfilled. In addition, the degree of coupling oxidative phosphorylation under these conditions corresponds to the economic degree of coupling qpec.

Adenosine Triphosphate↗
PubMed1982

Effects of parathyroid hormone on oxidative phosphorylation of heart mitochondria.

In an effort to understand the mechanism of action of parathyroid hormone (PTH) on the myocardium, we examined the effect of PTH on the function of isolated heart mitochondria. The hormone inhibited mitochondrial respiration in the presence of malate or beta-hydroxybutyrate but not succinate as substrates. It also inhibited phosphorylation and uncoupled oxidative phosphorylation. These effects of PTH were dose dependent and occurred only in the presence of calcium. A change in calcium concentration from zero to 2 mM did not affect mitochondrial function. PTH also stimulated mitochondrial ATPase. The inhibitory effect of PTH on mitochondrial respiration and on oxidative phosphorylation would result in decreased ATP synthesis and, hence, reduced availability of ATP. Such a sequence of events may provide an explanation for a potential long-term adverse effect of the hormone on the myocardium.

Animals↗
PubMed2004

The modeling of oxidative phosphorylation in skeletal muscle.

A computer model of oxidative phosphorylation was developed in isolated muscle mitochondria [Korzeniewski and Mazat: Biochem J 319: 143-148, 1996] and in intact skeletal muscle [Korzeniewski and Zoladz: Biophys Chem 92: 17-34, 2001]. Within this model the dependence on different metabolite concentrations of the rate of each enzymatic reaction, process and flux is described by an appropriate kinetic equation. The changes of metabolite concentrations over time are described by a set of ordinary differential equations. The model has been very extensively tested by a comparison of computer simulations with a broad set of experimental results concerning various kinetic properties of the oxidative phosphorylation system. Next the model was used for theoretical studies on the regulation of oxidative phosphorylation in intact muscle cells. The model decidedly supports the so-called parallel-activation mechanism or each-step-activation mechanism of adjusting the rate of ATP supply to the current energy demand [Korzeniewski: Biochem J 330: 1189-1195, 1998; Korzeniewski: Biochem J 375: 799-804, 2003]. Because of this mechanism, not only ATP usage, but also the substrate dehydrogenation system and all oxidative phosphorylation complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) are directly (and not by changes in metabolite concentrations) activated by some intracellular factor(s) related to muscle contraction, probably by calcium ions, during the transition from rest to work. This mechanism is able to account for several kinetic properties of oxidative phosphorylation that cannot be explained by other mechanisms postulated in the literature. Thus the discussed kinetic model of oxidative phosphorylation has appeared to be a very useful research tool.

Animals↗
PubMed2001

Mitochondrial oxidative phosphorylation system assembly in man: recent achievements.

The human oxidative phosphorylation system consists of five multi-subunit complexes of which the individual subunits, with the exception of complex II, are encoded either by mitochondrial or nuclear DNA. Consequently, a deficient enzyme activity of one or more of the complexes can be caused by mitochondrial or nuclear DNA mutations. In the past 5 years numerous mutations have been found in structural nuclear oxidative phosphorylation system genes. However, in a substantial number of patients with oxidative phosphorylation system complex deficiencies, despite extensive investigations, no mutations in the mitochondrial DNA or the structural nuclear genes have been found. Genetic defects in such patients are therefore suspected at the transcriptional, translational, post-translational level or in gene products involved in the assembly of the oxidative phosphorylation system. The latter is a complicated process, as the proteins encoded by the two genomes have to be brought together in a proper stoichiometric way to form five functional complexes. In the past year substantial progress in the knowledge of the human oxidative phosphorylation assembly process has been made. Several human assembly genes have been identified, and mutations in these genes responsible for human oxidative phosphorylation system complex-related diseases have been found. In this review, we summarize our current knowledge about human oxidative phosphorylation system assembly genes in health and disease.

Cytochrome-c Oxidase Deficiency↗
PubMed1992

Features of apparent nonchemiosmotic energization of oxidative phosphorylation by alkaliphilic Bacillus firmus OF4.

Oxidative phosphorylation by extremely alkaliphilic Bacillus species violates two major predictions of the chemiosmotic hypothesis: the magnitude of the chemiosmotic driving force, the delta p (electrochemical proton gradient), is too low to account for the phosphorylation potentials observed during growth at pH 10.5 without using a much higher H+/ATP stoichiometry than used during growth at pH 7.5, and artificially imposed diffusion potentials fail to energize ATP synthesis above about pH 9.5 (Guffanti, A. A., and Krulwich, T. A. (1989) Annu. Rev. Microbiol. 43, 435-463). To further examine the latter observation, large valinomycin-mediated potassium diffusion potentials were imposed across starved cells of Bacillus firmus OF4 at various pH values from pH 7.5 to 10.5. As the external pH increased above pH 8, there was a sharp decrease in the rate of ATP synthesis in response to an imposed diffusion potential. The rate of ATP synthesis fell to zero by pH 9.2 and 9.4, respectively, in the presence and absence of a small inwardly directed Na+ gradient. Electrogenic Na+/H+ antiport and Na+/alpha-aminoisobutyric acid symport proceeded at substantial rates throughout. When synthesis was energized by an electron donor, cells under comparable conditions synthesized ATP at rapid rates up to pH 10.5. The proton transfers that occur during respiration-dependent oxidative phosphorylation at pH 10.5 may depend upon specific complexes. Cells grown at pH 7.5, which have one-third the levels of the caa3-type terminal oxidase, and slightly lower levels of certain other respiratory chain complexes than pH 10.5-grown cells, support only low rates of ATP synthesis at pH 10.5, although energy-dependent symport and antiport rates are comparable with those in pH 10.5-grown cells. A model is presented for oxidative phosphorylation by the alkaliphilic Bacillus that involves a nonchemiosmotic direct intramembrane transfer of protons from specific respiratory chain complexes to the F0 sector of the ATPase, whereas remaining respiratory chain complexes extrude protons into the bulk to generate the bulk potential required both for ATP synthesis and other bioenergetic work. A pK-regulated gate or a delocalized proton pathway that fails to work above pH 9.5 are suggested as possible features that account for the loss of efficacy of a bulk-imposed diffusion potential in energizing ATP synthesis above pH 9.4.

Adenosine Triphosphate↗
PubMed1997

Source of ATP for hexokinase-catalyzed glucose phosphorylation in tumor cells: dependence on the rate of oxidative phosphorylation relative to that of extramitochondrial ATP generation.

We isolated highly intact and tightly coupled mitochondria from the rat ascites hepatoma cell line AH130 by disruption of the cell membrane by nitrogen cavitation. These isolated mitochondria were found to have essentially the same functional properties as rat liver mitochondria, but unlike the latter, hexokinase (HK) was bound to their membrane. Using the tumor mitochondrial preparation, we examined the source of ATP for phosphorylation of glucose by HK under conditions in which intra- and extramitochondrial ATP-generation systems operated separately or together. Results showed that the membrane-bound HK utilized ATP derived from the most efficiently operating ATP generation system, i.e., oxidative phosphorylation. However, when the rate of extramitochondrial ATP generation was much greater than that of oxidative phosphorylation, HK used ATP from the extramitochondrial ATP-generation system.

Adenosine Diphosphate↗