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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.

journal_name

Nat Med

journal_title

Nature medicine

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 RA,Krieg T,Brookes PS,Murphy MP

doi

10.1038/nm.3212

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

753-9

issue

6

eissn

1078-8956

issn

1546-170X

pii

nm.3212

journal_volume

19

pub_type

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