Proceedings of the National Academy of Sciences · 2009 · 218 citations · 13 references
Life SciencesBiochemistryPhysiologyMetabolismMitochondrial BiologyRedox BiochemistryCellular RespirationMitochondrial BiochemistryMitochondrial BioenergeticsMitochondrial FunctionMitochondrial PhysiologyRespiration InhibitionHypoxia Response In MitochondriaHypoxic PreconditioningMitochondrial Respiration ControlMitochondrial Respiration InhibitionMitochondrial Respiration SuppressionMitochondrial Respiratory Chain InhibitionMitochondrial TargetsMyocardial Ischemia-reperfusion Injury
Nitric oxide (NO(*)) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols (MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO(*) and S-nitrosated thiol proteins. MitoSNO1-induced NO(*) production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO(*) generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO(*) donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.
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Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1α
Thilo Hagen, Cormac T. Taylor, Francis Lam et al. · Science · 2003 · 704 citations