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

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

Research output: Contribution to journalArticlepeer-review

442 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)753-759
Number of pages7
JournalNature Medicine
Volume19
Issue number6
Early online date26 May 2013
DOIs
Publication statusPublished - Jun 2013
Externally publishedYes

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