Metabolic network control of oxidative phosphorylation: multiple roles of inorganic phosphate.
Phosphate (Pi) is a putative cytosolic signaling molecule in the regulation of oxidative phosphorylation. Here, by using a multiparameter monitoring system, we show that Pi controls oxidative phosphorylation in a balanced fashion, modulating both the generation of useful potential energy and the formation of ATP by F1F0-ATPase in heart and skeletal muscle mitochondria. In these studies the effect of Pi was determined on the mitochondria [NADH], NADH generating capacity, matrix pH, membrane potential, oxygen consumption, and cytochrome reduction level. Pi enhanced NADH generation and was obligatory for electron flow under uncoupled conditions. Pi oxidized cytochrome b (cyto-b) and reduced cytochrome c (cyto-c), potentially improving the coupling between the NADH free energy and the proton motive force. The apparent limitation in reducing equivalent flow between cyto-b and cyto-c in the absence of Pi was confirmed in the intact heart by using optical spectroscopic techniques under conditions with low cytosolic [Pi]. These results demonstrate that Pi signaling results in the balanced modulation of oxidative phosphorylation, by influencing both deltaGH+ generation and ATP production, which may contribute to the energy metabolism homeostasis observed in intact systems.
Bose
Salil
S
Laboratory of Cardiac Energetics, NHLBI, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
French
Stephanie
S
Evans
Frank J
FJ
Joubert
Fredric
F
Balaban
Robert S
RS
D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003580:Cytochromes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008027:Light; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D010710:Phosphates; D010766:Phosphorylation; D011522:Protons; D011817:Rabbits; D015398:Signal Transduction; D013053:Spectrophotometry; D013552:Swine; D013816:Thermodynamics; D013997:Time Factors
D003580:Cytochromes; D010710:Phosphates; D011522:Protons; D009243:NAD; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D010100:Oxygen