Nitric Oxide And Oxygen: Actions And Interactions In Health And Disease

Nitric oxide (NO) inhibits cell respiration reversibly and in competition with O₂ through 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 O₂ consumption. 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 O₂ towards non-respiratory O₂-dependent targets. This prevents the cell from registering a state of hypoxia at low O₂ concentrations. 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.