Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I (original) (raw)

Chouchani, E. T. et al. (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.Nature Medicine, 19(6), pp. 753-759. (doi: 10.1038/nm.3212) (PMID:23708290) (PMCID:PMC4019998)

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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 unclear1, 2, 3, 4, 5, 6. 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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Funder and Project Information

1

Developing chemical mass spectrometry probes to assess the production of reactive oxygen species in vivo

Richard Hartley

BB/I012826/1

CHEM - CHEMISTRY

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