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Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.

Nature medicine (2013-05-28)
Edward T Chouchani, Carmen Methner, Sergiy M Nadtochiy, Angela Logan, Victoria R Pell, Shujing Ding, Andrew M James, Helena M Cochemé, Johannes Reinhold, Kathryn S Lilley, Linda Partridge, Ian M Fearnley, Alan J Robinson, Richard C Hartley, Robin A J Smith, Thomas Krieg, Paul S Brookes, Michael P Murphy
RÉSUMÉ

Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not known, and it is unclear how this increase can be prevented. A wide variety of nitric oxide donors and S-nitrosating agents protect the ischemic myocardium from infarction, but the responsible mechanisms are unclear. Here we used a mitochondria-selective S-nitrosating agent, MitoSNO, to determine how mitochondrial S-nitrosation at the reperfusion phase of myocardial infarction is cardioprotective in vivo in mice. We found that protection is due to the S-nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage and tissue necrosis. Inhibition of complex I is afforded by the selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischemia. Our results identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy.

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