Faculty Opinions recommendation of Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.

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. PMID: 23708290 Funding information This work was supported by: Biotechnology and Biological Sciences Research Council, United Kingdom Grant ID: BB/I012923 Medical Research Council, United Kingdom Grant ID: MC_U105674181 British Heart Foundation, United Kingdom Grant ID: PG/12/42/29655 Medical Research Council, United Kingdom Grant ID: MC_U105663142 Wellcome Trust, United Kingdom Grant ID: 098565 NHLBI NIH HHS, United States Grant ID: R01-HL071158 CIHR, Canada NHLBI NIH HHS, United States Grant ID: R01 HL071158 More Less keyboard_arrow_down