Mitochondrial nitric oxide synthase

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Mitochondria produce nitric oxide (NO) through a Ca2+-sensitive mitochondrial NO synthase (mtNOS). The NO produced by mtNOS regulates mitochondrial oxygen consumption and transmembrane potential via a reversible reaction with cytochrome c oxidase. The reaction of this NO with superoxide anion yields peroxynitrite, which irreversibly modifies susceptible targets within mitochondria and induces oxidative and/or nitrative stress. In this article, we review the current understanding of the roles of mtNOS as a crucial biochemical regulator of mitochondrial functions and attempt to reconcile apparent discrepancies in the literature on mtNOS.

Section snippets

Discovery of mitochondrial nitric oxide synthase

The discovery that the endothelium-derived relaxing factor is nitric oxide (NO) [1] opened new horizons in biomedical research. The cellular synthesis of NO is catalyzed by NO synthase (NOS) isozymes, three of which are well characterized. Although expression of these enzymes is not tissue specific, they are referred to as neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Each isozyme consumes l-arginine, produces equal amounts of NO and l-citrulline, and requires Ca2+

mtNOS and the regulation of mitochondrial functions

Electrons flow down the mitochondrial respiratory chain following the redox-potential hierarchy of the respiratory complexes and reduce O2 to H2O at the terminal member of the chain, cytochrome c oxidase. Coupled to the electron flow, protons are pumped from the mitochondrial matrix into the intermembrane space. The chemiosmotic principle, which was established by the pioneering work of Mitchell in the 1950s [16], postulates two immediate consequences of this proton extrusion. These are an

Which NOS isozyme is mtNOS?

The only effort to purify and characterize the amino acid sequence of mtNOS used mitochondria from rat liver. A protein from the mitochondrial matrix of rat liver that generates l-citrulline from l-arginine in a Ca2+-independent manner has been purified using ADP-affinity chromatography [21]. Because the purified protein cross-reacts with an antibody to iNOS (which also generates l-citrulline from l-arginine in a Ca2+-insensitive manner) it was concluded that mtNOS was iNOS. However, it must be

NO in mitochondria

Of the electrons that flow through the respiratory chain, ∼2–5% leak out 44, 45. These electrons account for the fraction of the total oxygen that is consumed by mitochondria to generate superoxide anion and hydrogen peroxide. Although the chemical reactivity of superoxide anion is modest, its reaction with NO with the rate constant of 1.9×1010 M s−1 [46] is nearly diffusion-controlled and results in the formation of peroxynitrite, a highly reactive NO-derived species. Mitochondria provide the

Concluding remarks

The first report on mtNOS activity in 1997 stimulated several laboratories to study this enzyme. By competing for the O2-binding site of cytochrome c oxidase, NO produced by mtNOS modulates mitochondrial respiration, Δψ and ΔpH, and, thus, regulates mitochondrial bioenergetics. NO produced by mtNOS can generate peroxynitrite, which induces oxidative and/or nitrative stress and the release of cytochrome c from mitochondria in addition to inactivation of susceptible mitochondrial enzymes. These

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