Journal
NATURE MEDICINE
Volume 19, Issue 6, Pages 753-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nm.3212
Keywords
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Funding
- UK Medical Research Council
- UK Biotechnology and Biological Sciences Research Council [BB/I012923]
- Gates Cambridge Trust
- Canadian Institutes of Health Research
- British Heart Foundation [PG/12/42/29655]
- US National Institutes of Health [R01-HL071158]
- International Society for Heart Research (ISHR-ES/SERVIER research fellowship)
- BBSRC [BB/I012826/1, BB/I012923/1] Funding Source: UKRI
- MRC [MC_U105663142, MC_U105674181] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I012923/1, BB/I012826/1] Funding Source: researchfish
- British Heart Foundation [PG/12/42/29655] Funding Source: researchfish
- Medical Research Council [MC_U105674181, MC_U105663142] Funding Source: researchfish
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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(1-6). 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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