Nitric Oxide And Oxygen: Actions And Interactions In Health And Disease.
Nitric oxide (NO) inhibits cell respiration reversibly and in competition with O2through the inhibition of the mitochondrial cytochrome c oxidase (Complex IV). At concentrations lower than those required to inhibit respiration, endogenous NO enhances the reduction of the electron transport chain, thus enabling cells to maintain their O2consumption. This however facilitates the release of superoxide anion, which initiates the transcriptional activation of NF-kB as an early signal of a stress response. Through free radical formation, long-term inhibition of mitochondrial respiration by NO leads to persistent inhibition of Complex I. This is dependent on the S-nitrosylation of a specific thiol in the active form of this protein. S-nitrosylation of Complex I might indicate the early stages of a pathological process. Inhibition of mitochondrial respiration by low concentrations of NO at critical O2 concentrations also leads to prevention of the stabilization of hypoxia-inducible factor-1α (HIF-1α) due to the redistribution of O2towards non-respiratory O2-dependent targets. This prevents the cell from registering a state of hypoxia at low O2concentrations. On the other hand, at higher concentrations such as those generated in certain forms of cancer, NO increases the expression of HIF-1α by an action most probably involving a free radical mechanism. It is likely that the interactions between oxygen and NO, either at the mitochondria or in the cell in general, play a role in the initiation and development of neoplastic transformation and spreading. The ways in which these interactions operate remain unclear and are likely to vary from cancer to cancer.
Director of Cancer Sciences, University of Manchester, Wolfson Molecular Imaging Centre, UK.
Professor Sir Salvador
PS
Moncada
D000818:Animals; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009569:Nitric Oxide; D003576:Electron Transport Complex IV; D010100:Oxygen