Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology

Abstract

Cooper CE, Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology. Am J Physiol Cell Physiol 292: C1993-C2003, 2007. First published February 28, 2007 doi:10.1152/ajpcell.00310.2006 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 (a3) and copper (CuB) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a3) and oxygen-independent (at CuB) 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. mitochondria; cytochrome oxidase NITRIC OXIDE (NO) is known as an intercellular messenger, synthesized in mammalian systems from arginine, NADPH, and oxygen by the NO synthase (NOS) class of enzymes (1). It has a wide range of physiological functions, most notably the control of blood pressure and blood flow (46, 63) mediated by the production of cGMP via its activation of the heme enzyme, soluble guanylate cyclase (45).Just over a decade ago, several groups demonstrated that the primary target for NO interactions with mammalian mitochondria is at the level of the oxygen-consuming enzyme, cytochrome c oxidase (15,20,73). These, and numerous subsequent studies, have demonstrated that in vitro cytochrome c oxidase is reversibly inhibited by nanomolar levels of NO. The possible cellular consequences of this effect are described in our previous paper (38). This review will instead focus on the importance of NO interactions with cytochrome oxidase at levels of organization above that of the individual cell.Two major questions arise when contemplating the possible consequences of this interaction at the tissue/organ level. First, does it occur in vivo? Second, if so, what are the physiological consequences? Whereas the detailed molecular mechanism of inhibition might appear to be of more interest to biochemists than physiologists, un...

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