NO Regulates Mitochondrial Respiration

NO inhibits mitochondrial function through different mechanisms. Short-term exposures to physiologic concentrations of NO rapidly inhibit complex IV (cytochrome C oxidase) in a reversible and physiologic way by competition with O2.77 Cardiac hypertrophy increases sensitivity of mitochondrial respiration to complex IV inhibition by NO, and together with increased iNOS expression, may favor the development of heart failure in rats.78 NO also inhibits mitochondrial creatine kinase coupled to oxidative phosphorylation, leading to a decreased sensitivity of mitochondrial respiration to ADP, thereby reducing ATP formation.79

NO may decrease contractile reserves through inhibition of cytosolic creatine kinase.80 Prolonged exposure to NO results in persistent inhibition of complex I via S-nitrosylation.77 Endogenous peroxynitrite formation also can cause an irreversible inhibition of multiple respiratory complexes, activating the proton leak and permeability transition pore, decreasing mitochondrial respiration, and reducing contractility.81

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