Nitric Oxide Synthesis in the Mitochondria of Animal Cells

Abstract

Several studies have pointed out that NO affects distinct functions of the mitochondria, such as oxidative phosphorylation, free radical generation, membrane potential and the mitochondrial pathway of apoptosis (Mitochondrion 3:187–204, 2004; Arterioscler Thromb Vasc Biol 30:643–647, 2010). The inhibitory effect of NO on mitochondrial respiration has been documented in various cell types (FEBS Lett 345:50–54, 1994; Biochem Biophys Res Commun 218:40–44, 1996; FEBS Lett 417:75–80, 1997; FEBS Lett 446:261–263, 1999). The underlying mechanism is the competitive and reversible inhibition of cytochrome-c oxidase (CcO, Complex IV) and the S-nitrosylation of electron transport chain proteins (FEBS Lett 345:50–54, 1994; Arch Biochem Biophys 328:85–92, 1996; Proc Natl Acad Sci USA 95:7631–7636, 1998). Although NO competes with O₂ at CcO and thus inhibits respiration, CcO eliminates NO by oxidizing it to NO₂ ⁻ under normoxia (Trends Biochem Sci 27:33–39, 2002; J Bioenerg Biomembr 40:533–539, 2008) (Fig. 10.1). Moreover, in the presence of O₂ ⁻, NO forms ONOO⁻, thus the previously inhibited CcO is being reactivated (Arch Biochem Biophys 328:85–92, 1996). NO also mitigates CcO release and administering l-arginine and NOS-cofactors to isolated rat mitochondria increases mitochondrial respiration (Dev Neurosci 15:165–173, 1993; J Biol Chem 275:20474–20479, 2000). The effects of NO on the mitochondrial respiration depend on the local NO, O₂ ⁻ and ONOO⁻ concentrations (Fig. 10.2). For instance, in normoxic cells NO binds to guanylyl cyclase with much higher affinity than to CcO (Biochem J 405:223–231, 2007) and the inhibitory effect of NO on CcO becomes prominent under O₂ limitations, when the reductive NO synthesis increases (Arterioscler Thromb Vasc Biol 30:643–647, 2010). A sustained mitochondrial NO level may initiate hypoxic signaling and adaptation of the respiratory electron chain to hypoxia (Free Radic Biol Med 33:755–764, 2002; Exp Biol Med (Maywood) 234:1020–1028, 2009) (Fig. 10.1). A possible NO release from the hypoxic cells can evoke local vasodilation and reoxygenation of the affected tissue (Proc Natl Acad Sci USA 104:18508–18513, 2007; Arterioscler Thromb Vasc Biol 30:643–647, 2010).