title: Regulation of cytochrome c oxidase by adenylic nucleotides. Is oxidative phosphorylation feedback regulated by its end-products?
abstract: Cytochrome c oxidase, which catalyzes an irreversible step of the respiratory chain, is one of the rate-controlling steps of oxidative phosphorylation on isolated mitochondria. The rate of electron transfer through the complex is primarily controlled by the associated thermodynamic forces, i.e., the span in redox potential between oxygen and cytochrome c and the protonmotive force. However, the electron flux also depends on the various kinetic effectors, including adenylic nucleotides. Although the number of binding sites for ATP and ADP on cytochrome oxidase is still a matter of debate, experiments performed on the solubilized and reconstituted enzyme provide strong functional evidence that the mammalian cytochrome c oxidase binds adenylic nucleotides on both sides of the inner membrane. These effects include modification in cytochrome c affinity, allosteric inhibition and changes in proton pumping efficiency. Immunological studies have pointed out the role of subunit IV and that of an ATP-binding protein, subunit VIa, in these kinetic regulations. In yeast, the role of the nuclear-encoded subunits in assembly and regulation of the cytochrome c oxidase has been further substantiated by using gene-disruption analysis. Using a subunit VIa-null mutant, the consequences of the ATP regulation on oxidative phosphorylation have been further investigated on isolated mitochondria. Taken together, the data demonstrate that there are multiple regulating sites for ATP on the yeast cytochrome oxidase with respect to the location (matrix versus cytosolic side), kinetic effect (activation versus inhibition) and consequence on the flow-force relationships. The question is therefore raised as to the physiological meaning of such feedback regulation of the respiratory chain by ATP in the control and regulation of cellular energy metabolism.
authors.affiliation: Institut de Biochimie et de Génétique Cellulaires, Université V. Segalen-CNRS, Bordeaux, France.
authors.forename: B
authors.initials: B
authors.lastname: Beauvoit
authors.forename: M
authors.initials: M
authors.lastname: Rigoulet
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D010085:Oxidative Phosphorylation; D011487:Protein Conformation; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000201:enzymology / Q000235:genetics
chemical_list: D000227:Adenine Nucleotides; D021122:Protein Subunits; D003576:Electron Transport Complex IV