title: Nitric oxide regulation of mitochondrial oxygen consumption II: Molecular mechanism and tissue physiology.
abstract: Nitric oxide (NO) is an intercellular signaling molecule; among its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen-consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and the consequences for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron (a(3)) and copper (Cu(B)) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a(3)) and oxygen-independent (at Cu(B)) manner. Before inhibition of oxygen consumption, changes can be observed in enzyme and substrate (cytochrome c) redox state. Physiological consequences can be mediated either by direct "metabolic" effects on oxygen consumption or via indirect "signaling" effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of NO synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding, in physiology is still awaited.
authors.affiliation: Dept. of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom. ccooper@essex.ac.uk
authors.forename: Chris E
authors.initials: CE
authors.lastname: Cooper
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
mesh_terms: D000818:Animals; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; D010100:Oxygen