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, 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

Full text not available from this repository.

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.

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
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	30 Sep 2022 15:31
Last Modified:	06 Feb 2025 10:59
URI:	https://ueaeprints.uea.ac.uk/id/eprint/88749
DOI:	10.1038/nm.3212

Actions (login required)

View Item