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

TitleCardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.
Publication TypeJournal Article
Year of Publication2013
AuthorsChouchani, 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
JournalNat Med
Volume19
Issue6
Pagination753-9
Date Published2013 Jun
ISSN1546-170X
KeywordsAnimals, 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.

DOI10.1038/nm.3212
Alternate JournalNat. Med.
Citation Key10.1038/nm.3212
PubMed ID23708290
PubMed Central IDPMC4019998
Grant List098565 / / Wellcome Trust / United Kingdom
BB/I012826/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/I012923 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/I012923/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
MC_U105674181 / / Medical Research Council / United Kingdom
PG/12/42/29655 / / British Heart Foundation / United Kingdom
R01 HL071158 / HL / NHLBI NIH HHS / United States
R01-HL071158 / HL / NHLBI NIH HHS / United States
/ / Medical Research Council / United Kingdom
/ / Canadian Institutes of Health Research / Canada