Abstract
See related article, pages 1178–1183 The discovery that a high-affinity heme ligand, nitric oxide (NO), was a critical regulator of vasodilation, hemostasis, and vascular inflammation, immediately presented a number of stark paradoxes. Most notably, the formation of NO in endothelium and tissue could increase oxygen delivery to tissue by direct vasodilation and recruitment of oxygen rich blood but paradoxically could compete directly with critical oxygen binding sites on oxygen carrier and storage proteins (ie, hemoglobin and myoglobin) and on heme proteins of the mitochondrial electron transport chain (METC). Consistent with such an activity for NO, it was recognized that NO binds with relatively high affinity to cytochrome c oxidase (complex IV) of the METC.1–3 Thus, the paradox: why would a molecule that is apparently essential for vasodilation and oxygen delivery directly bind to and inhibit mitochondrial electron transport? Such an activity, by inhibition of respiration and subsequent ATP generation, could represent an innate poison pill, analogous to cyanide. Interestingly, the binding of NO to cytochrome c oxidase is unique for 2 major reasons (1) Unlike the binding of NO to deoxyhemoglobin or myoglobin, which has a very low dissociation rate, the binding of NO to cytochrome c oxidase is reversible; NO is released as the enzyme cycles. This means that NO-dependent inhibition of respiration is reversible.1,3 (2) Perhaps more importantly, the binding of NO to cytochrome c oxidase is regulated by oxygen, such that NO is a more potent inhibitor of respiration as oxygen tension decreases.1,3,4 The binding of NO to cytochrome c oxidase and the resultant inhibition of respiration would seem detrimental, because ATP depletion would ensue. Indeed, in cases of excessive NO generation, complete inhibition of cytochrome c oxidase has been shown to contribute to pathology.5 However, at physiological concentrations of NO (such …
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have