Trends in Pharmacological Sciences
Mitochondrial nitric oxide synthase
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
References (67)
Endothelial type nitric oxide synthase in skeletal muscle fibers: mitochondrial relationships
Biochem. Biophys. Res. Commun.
(1995)Immunocytochemical evidence for a mitochondrially located nitric oxide synthase in brain and liver
Biochem. Biophys. Res. Commun.
(1995)Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation?
Biochem. Biophys. Res. Commun.
(1996)Mitochondrial nitric oxide synthase is constitutively active and is functionally upregulated in hypoxia
Free Radic. Biol. Med.
(2001)Docking of endothelial nitric oxide synthase (eNOS) to the mitochondrial outer membrane: a pentabasic amino acid sequence in the autoinhibitory domain of eNOS targets a proteinase K-cleavable peptide on the cytoplasmic face of mitochondria
J. Biol. Chem.
(2004)Localization of nitric oxide synthase in human skeletal muscle
Biochem. Biophys. Res. Commun.
(1996)- et al.
Subcellular localization of neuronal nitric oxide synthase in the brain of a teleost; an immunoelectron and confocal microscopical study
Brain Res.
(1997) The modulation of mitochondrial nitric-oxide synthase activity in rat brain development
J. Biol. Chem.
(2002)Biochemistry of mitochondrial nitric-oxide synthase
J. Biol. Chem.
(2002)- et al.
Nitric oxide synthase activity in mitochondria
FEBS Lett.
(1997)
Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension
Biochem. Biophys. Res. Commun.
Purification and characterization of a nitric-oxide synthase from rat liver mitochondria
J. Biol. Chem.
Mitochondrial nitric oxide synthase
Mitochondrion
Mitochondrial nitric oxide synthase is not eNOS, nNOS or iNOS
Free Radic. Biol. Med.
Synergistic deleterious effect of micromolar Ca ions and free radicals on respiratory function of heart mitochondria at cytochrome C and its salvage trial
Neuroscience
Mitochondrial nitric-oxide synthase stimulation causes cytochrome c release from isolated mitochondria. Evidence for intramitochondrial peroxynitrite formation
J. Biol. Chem.
Determination of the matrix free Ca2+ concentration and kinetics of Ca2+ efflux in liver and heart mitochondria
J. Biol. Chem.
Calcium-containing mitochondrial granules in neurohypophysial axon terminals disappear following vasopressin treatment of Brattleboro rats
Neurosci. Lett.
The comeback of mitochondria to calcium signalling
Cell Calcium
Regulation of rat liver carbamyl phosphate synthetase I. Inhibition by metal ions and activation by amino acids and other chelating agents
J. Biol. Chem.
Brain mitochondrial nitric oxide synthase: in vitro and in vivo inhibition by chlorpromazine
Arch. Biochem. Biophys.
The regulation of mitochondrial oxygen uptake by redox reactions involving nitric oxide and ubiquinol
J. Biol. Chem.
Peroxynitrite formed by mitochondrial NO synthase promotes mitochondrial Ca2+ release
Free Radic. Biol. Med.
The role of mitochondrial nitric oxide synthase in inflammation and septic shock
Free Radic. Biol. Med.
Oxygen dependence of mitochondrial nitric oxide synthase activity
Biochem. Biophys. Res. Commun.
Peroxynitrite: reactive, invasive and enigmatic
Curr. Opin. Chem. Biol.
Topology of superoxide production from different sites in the mitochondrial electron transport chain
J. Biol. Chem.
Reactions of peroxynitrite in the mitochondrial matrix
Free Radic. Biol. Med.
Inhibition of S-nitrosation of reduced glutathione in aerobic solutions of nitric oxide by phosphate and other inorganic anions
Biochem. Pharmacol.
Seleno compounds and glutathione peroxidase catalyzed decomposition of S-nitrosothiols
Biochem. Biophys. Res. Commun.
S-nitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide
J. Biol. Chem.
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor
Nature
Compartmentalized nitrosation and nitration in mitochondria
Antioxid. Redox Signal.
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