Title | Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Chouchani, ET, Methner, C, Nadtochiy, SM, Logan, A, Pell, VR, Ding, S, James, AM, Cochemé, HM, Reinhold, J, Lilley, KS, Partridge, L, Fearnley, IM, Robinson, AJ, Hartley, RC, Smith, RAJ, Krieg, T, Brookes, PS, Murphy, MP |
Journal | Nat Med |
Volume | 19 |
Issue | 6 |
Pagination | 753-9 |
Date Published | 2013 Jun |
ISSN | 1546-170X |
Keywords | Animals, Cysteine, Electron Transport Complex I, Male, Mice, Mice, Inbred C57BL, Mitochondria, Heart, Mitochondrial Proteins, Myocardial Reperfusion Injury, Nitrosation, Protein Subunits, Rats, Reactive Oxygen Species |
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. |
DOI | 10.1038/nm.3212 |
Alternate Journal | Nat. Med. |
Citation Key | 10.1038/nm.3212 |
PubMed ID | 23708290 |
PubMed Central ID | PMC4019998 |
Grant List | PG/12/42/29655 / / British Heart Foundation / United Kingdom R01 HL071158 / HL / NHLBI NIH HHS / United States BB/I012923 / / Biotechnology and Biological Sciences Research Council / United Kingdom R01-HL071158 / HL / NHLBI NIH HHS / United States / / Canadian Institutes of Health Research / Canada 098565 / / Wellcome Trust / United Kingdom MC_U105663142 / / Medical Research Council / United Kingdom MC_U105674181 / / Medical Research Council / United Kingdom |