title: Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology.
abstract: Mitochondrial biochemistry is complex, expanding from oxygen consumption, oxidative phosphorylation, lipid catabolism, heme biosynthesis, to apoptosis, calcium homeostasis, and production of reactive oxygen species, including nitric oxide (NO). The latter molecule is produced by a mitochondrial NO synthase (mtNOS). The rates of consumption and production determine the steady-state concentration of NO at subcellular levels, leading to regulation of mitochondrial events. Temporospatial processes tightly regulate production of NO in mitochondria to maximize target effects and minimize deleterious reactions. Temporal regulatory mechanisms of mtNOS include activation by calcium signaling and transcriptional/translational regulations. Calcium-activated mtNOS inhibits mitochondrial respiration, resulting in a decrease of the oxygen consumption. This negative regulation antagonizes the effects of calcium on calcium-dependent dehydrogenases in the citric acid cycle, preventing the formation of anoxic foci. Temporal regulation of NO production by intracellular calcium signaling is a complex process, considering the heterogeneous intracellular calcium response and distribution. NO production in mitochondria is spatially regulated by mechanisms that determine subcellular localization of mtNOS, likely acylation and protein-protein interactions, in addition to transcriptional regulation as neuronal NOS. Because NO rapidly decays in mitochondria, subcellular localization of mtNOS is crucial for NO to function as a signal molecule. These temporospatial processes are biologically important to allow NO to act as an effective signal molecule to regulate mitochondrial events such as oxygen consumption and reactive oxygen species production.
authors.affiliation: University of California, Department of Molecular Biosciences, Davis, California 95616. cgiulivi@ucdavis.edu
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kato
authors.forename: Christopher Eric
authors.initials: CE
authors.lastname: Cooper
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D013997:Time Factors
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen; D002118:Calcium