Regulation of oxidative phosphorylation in intact mammalian heart in vivo.

A dynamic computer model of oxidative phosphorylation in intact heart was developed by modifying the model of oxidative phosphorylation in intact skeletal muscle published previously. Next, this model was used for theoretical studies on the regulation of oxidative phosphorylation in intact heart in vivo during transition between different work intensities. It is shown that neither a direct activation of ATP usage alone nor a direct activation of both ATP usage and substrate dehydrogenation, including the calcium-activated tricarboxylate acid cycle dehydrogenases, can account for the constancy of [ADP], [PCr], [P(i)] and [NADH] during a significant increase in oxygen consumption and ATP turnover encountered in intact heart in vivo. Only a direct activation of all oxidative phosphorylation complexes in parallel with a stimulation of ATP usage and substrate dehydrogenation enabled to reproduce the experimental data concerning the constancy of metabolite concentrations. The molecular background of the differences between heart and skeletal muscle in the kinetic behaviour of the oxidative phosphorylation system is also discussed.

[1]  R. Hansford.  Control of Mitochondrial Substrate Oxidation , 1980 .

[2]  B. Korzeniewski.  Theoretical studies on the regulation of oxidative phosphorylation in intact tissues. , 2001, Biochimica et biophysica acta.

[3]  B Korzeniewski,et al.  Theoretical studies on the control of oxidative phosphorylation in muscle mitochondria: application to mitochondrial deficiencies. , 1996, The Biochemical journal.

[4]  Reinhart Heinrich,et al.  A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. , 1974, European journal of biochemistry.

[5]  C Reder,et al.  Metabolic control theory: a structural approach. , 1988, Journal of theoretical biology.

[6]  Icksoo Lee,et al.  Control of mitochondrial membrane potential and ROS formation by reversible phosphorylation of cytochrome c oxidase , 2002, Molecular and Cellular Biochemistry.

[7]  B. Kholodenko,et al.  Ca2+ stimulates both the respiratory and phosphorylation subsystems in rat heart mitochondria. , 1996, The Biochemical journal.

[8]  Marko Vendelin,et al.  Analysis of functional coupling: mitochondrial creatine kinase and adenine nucleotide translocase. , 2004, Biophysical journal.

[9]  K. Sahlin,et al.  Rate of oxidative phosphorylation in isolated mitochondria from human skeletal muscle: effect of training status. , 1997, Acta physiologica Scandinavica.

[10]  J. Mccormack,et al.  Role of calcium ions in regulation of mammalian intramitochondrial metabolism. , 1990, Physiological reviews.

[11]  R. Balaban,et al.  Effects of afterload and heart rate on NAD(P)H redox state in the isolated rabbit heart. , 1993, The American journal of physiology.

[12]  J. V. van Beek,et al.  Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate. , 1994, Circulation research.

[13]  D. Harris,et al.  Control of mitochondrial ATP synthesis in the heart. , 1991, The Biochemical journal.

[14]  M. Vendelin,et al.  Functional coupling as a basic mechanism of feedback regulation of cardiac energy metabolism , 2004, Molecular and Cellular Biochemistry.

[15]  G. Brown,et al.  Nitric oxide and mitochondrial respiration. , 1999, Biochimica et biophysica acta.

[16]  H. Kacser,et al.  A universal method for achieving increases in metabolite production. , 1993, European journal of biochemistry.

[17]  M. Vendelin,et al.  Regulation of mitochondrial respiration in heart cells analyzed by reaction-diffusion model of energy transfer. , 2000, American journal of physiology. Cell physiology.

[18]  J. Cheung,et al.  Ratiometric methodology for NAD(P)H measurement in the perfused rat heart using surface fluorescence. , 1994, The American journal of physiology.

[19]  R. Winslow,et al.  An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. , 2003, Biophysical journal.

[20]  M. Brand,et al.  Calcium regulation of oxidative phosphorylation in rat skeletal muscle mitochondria. , 2000, Biochimica et biophysica acta.

[21]  M. Chandler,et al.  Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation , 2005, The Journal of physiology.

[22]  B. Korzeniewski,et al.  Factors determining the oxygen consumption rate (VO2) on-kinetics in skeletal muscles. , 2004, The Biochemical journal.

[23]  J. Mazat,et al.  Control of oxidative phosphorylation in rat muscle mitochondria: implications for mitochondrial myopathies. , 1993, Biochimica et biophysica acta.

[24]  B Korzeniewski,et al.  Regulation of ATP supply during muscle contraction: theoretical studies. , 1998, The Biochemical journal.

[25]  B. Korzeniewski,et al.  Training-induced adaptation of oxidative phosphorylation in skeletal muscles. , 2003, The Biochemical journal.

[26]  D. Allen,et al.  Myocardial contractile function during ischemia and hypoxia. , 1987, Circulation research.

[27]  J. Schaper,et al.  Ultrastructural Morphometric Analysis of Myocardium from Dogs, Rats, Hamsters, Mice, and from Human Hearts , 1985, Circulation research.

[28]  R S Balaban,et al.  Relation between phosphate metabolites and oxygen consumption of heart in vivo. , 1989, The American journal of physiology.

[29]  V. Mootha,et al.  Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the F0/F1-ATPase , 2000 .

[30]  H V Westerhoff,et al.  The Signal Transduction Function for Oxidative Phosphorylation Is at Least Second Order in ADP* , 1996, The Journal of Biological Chemistry.

[31]  B CHANCE,et al.  The respiratory chain and oxidative phosphorylation. , 1956, Advances in enzymology and related subjects of biochemistry.

[32]  M. Brand,et al.  Proportional activation coefficients during stimulation of oxidative phosphorylation by lactate and pyruvate or by vasopressin. , 1995, Biochimica et biophysica acta.

[33]  B Korzeniewski,et al.  Regulation of ATP supply in mammalian skeletal muscle during resting state-->intensive work transition. , 2000, Biophysical chemistry.

[34]  Control of Mitochondrial Respiration in the Heart In Vivo , 1990 .

[35]  W. Kunz,et al.  Distribution of flux control among the enzymes of mitochondrial oxidative phosphorylation in calcium-activated saponin-skinned rat musculus soleus fibers. , 1995, European journal of biochemistry.

[36]  B. Korzeniewski,et al.  A model of oxidative phosphorylation in mammalian skeletal muscle. , 2001, Biophysical chemistry.

[37]  D A Fell,et al.  Physiological control of metabolic flux: the requirement for multisite modulation. , 1995, The Biochemical journal.

[38]  H. Kacser,et al.  The control of flux. , 1995, Biochemical Society transactions.

[39]  A. From,et al.  Regulation of the oxidative phosphorylation rate in the intact cell. , 1990, Biochemistry.

[40]  Y. Usson,et al.  Heterogeneity of ADP diffusion and regulation of respiration in cardiac cells. , 2003, Biophysical journal.

[41]  C. Malloy,et al.  Respiratory control and substrate effects in the working rat heart. , 1992, The Biochemical journal.

[42]  R. Kauppinen,et al.  Subcellular distribution of phosphagens in isolated perfused rat heart , 1980, FEBS letters.

[43]  C. Cooper.  Nitric oxide and cytochrome oxidase: substrate, inhibitor or effector? , 2002, Trends in biochemical sciences.

[44]  R. Kauppinen,et al.  Proton electrochemical potential of the inner mitochondrial membrane in isolated perfused rat hearts, as measured by exogenous probes. , 1983, Biochimica et biophysica acta.

[45]  B. Wittenberg,et al.  NADH fluorescence of isolated ventricular myocytes: effects of pacing, myoglobin, and oxygen supply. , 1993, Biophysical journal.

[46]  R S Balaban,et al.  Relation between work and phosphate metabolite in the in vivo paced mammalian heart. , 1986, Science.

[47]  G. Salama,et al.  Effects of cardiac work on electrical potential gradient across mitochondrial membrane in perfused rat hearts. , 1993, The American journal of physiology.

[48]  D. Fell,et al.  Control of glucose utilization in working perfused rat heart. , 1994, The Journal of biological chemistry.

[49]  V. Saks,et al.  Compartmentalized energy transfer in cardiomyocytes: use of mathematical modeling for analysis of in vivo regulation of respiration. , 1997, Biophysical journal.

[50]  B. Korzeniewski.  Regulation of oxidative phosphorylation in different muscles and various experimental conditions. , 2003, The Biochemical journal.

[51]  J. Mazat,et al.  Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases. , 2000, The Biochemical journal.