title: Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.
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.
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Chouchani
authors.forename: Carmen
authors.initials: C
authors.lastname: Methner
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Pell
authors.forename: Shujing
authors.initials: S
authors.lastname: Ding
authors.forename: Andrew M
authors.initials: AM
authors.lastname: James
authors.forename: Helena M
authors.initials: HM
authors.lastname: Cochemé
authors.forename: Johannes
authors.initials: J
authors.lastname: Reinhold
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Lilley
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.forename: Ian M
authors.initials: IM
authors.lastname: Fearnley
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Robinson
authors.forename: Richard C
authors.initials: RC
authors.lastname: Hartley
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D015538:Nitrosation; D021122:Protein Subunits; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I; C114961:MT-ND3 protein, human; D003545:Cysteine