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

Chouchani, Edward T., Methner, Carmen, Nadtochiy, Sergiy M., Logan, Angela, Pell, Victoria R., Ding, Shujing, James, Andrew M., Cochemé, Helena M., Reinhold, Johannes ORCID:, Lilley, Kathryn S., Partridge, Linda, Fearnley, Ian M., Robinson, Alan J., Hartley, Richard C., Smith, Robin A. J., Krieg, Thomas, Brookes, Paul S. and Murphy, Michael P. (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nature Medicine, 19 (6). pp. 753-759. ISSN 1078-8956

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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.

Item Type: Article
Additional Information: Funding Information: This study was supported by the UK Medical Research Council and grants from the UK Biotechnology and Biological Sciences Research Council (BB/I012923 to M.P.M. and R.C.H.), the Gates Cambridge Trust and the Canadian Institutes of Health Research (doctoral scholarship and postdoctoral fellowship to E.T.C.), the British Heart Foundation (PG/12/42/29655 to T.K.), the US National Institutes of Health (R01-HL071158 to P.S.B.) and the International Society for Heart Research (ISHR-ES/SERVIER research fellowship to C.M.). We thank L. Sazanov and J. Hirst for helpful discussions.
Uncontrolled Keywords: biochemistry, genetics and molecular biology(all) ,/dk/atira/pure/subjectarea/asjc/1300
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Depositing User: LivePure Connector
Date Deposited: 30 Sep 2022 15:31
Last Modified: 21 Oct 2022 15:31
DOI: 10.1038/nm.3212

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