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: Edward T Chouchani, Carmen Methner, Sergiy M Nadtochiy, Angela Logan, Victoria R Pell, Shujing Ding, Andrew M James, Helena M Cochemé, Johannes Reinhold, Kathryn S Lilley, Linda Partridge, Ian M Fearnley, Alan J Robinson, Richard C Hartley, Robin A J Smith, Thomas Krieg, Paul S Brookes, Michael P Murphy
• Journal: Nature medicine (Nat Med) Vol. 19 Issue 6 Pg. 753-9 (Jun 2013) ISSN: 1546-170X [Electronic] United States
• PMID: 23708290 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mitochondrial Proteins
• Protein Subunits
• Reactive Oxygen Species
• Electron Transport Complex I
• MT-ND3 protein, human
• Cysteine

Topics

• Animals
• Cysteine (metabolism)
• Electron Transport Complex I (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria, Heart (metabolism)
• Mitochondrial Proteins (metabolism)
• Myocardial Reperfusion Injury (prevention & control)
• Nitrosation
• Protein Subunits
• Rats
• Reactive Oxygen Species (metabolism)