Abstract
In this study, we have analyzed the effect of different cardioprotective complex II inhibitors on the mitochondrial production of reactive oxygen species (ROS) because ROS seem to be essential for signaling during preconditioning to prevent ischemia/reperfusion injury. Despite different binding sites and concentrations required for half-maximal inhibition—ranging from nanomolar for the Q site inhibitor atpenin A5 to millimolar for the succinate analog malonate—all inhibitors modulated ROS production in the same ambivalent fashion: they promoted the generation of superoxide at the Qo site of complex III under conditions of “oxidant-induced reduction” but attenuated ROS generated at complex I due to reverse electron transfer. All inhibitors showed these ambivalent effects independent of the presence of K+. These findings suggest a direct modulation of mitochondrial ROS generation during cardioprotection via complex II inhibition and question the recently proposed role of complex II as a regulatory component of the putative mitochondrial KATP channel.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the Deutsche Forschungsgemeinschaft [Grant SFB 815 Redox-Regulation, Project A2].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.070342.
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ABBREVIATIONS:
- ROS
- reactive oxygen species
- DQA
- SAN 549, 2-n-decyl-quinazolin-4-yl-amine
- FCCP
- carbonyl-cyanide-p-trifluoro-methoxy-phenylhydrazone
- HRP
- horseradish peroxidase
- mitoKATP
- mitochondrial ATP-sensitive K+
- Q-pool
- ubiquinone pool
- RET
- reverse electron transfer
- RHM
- rat heart mitochondria
- SMP
- submitochondrial particle
- TTFA
- 2-thenoyltrifluoroacetone.
- Received December 4, 2010.
- Accepted January 28, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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