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J. Biol. Chem., Vol. 281, Issue 19, 13159-13168, May 12, 2006

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Direct and Indirect Roles of Cytochrome b in the Mediation of Superoxide Generation and NO Catabolism by Mitochondrial Succinate-Cytochrome c Reductase^*

Yeong-Renn Chen¹, Chwen-Lih Chen, Alexander Yeh, Xiaoping Liu, and Jay L. Zweier

From the Davis Heart & Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, and the Department of Molecular and Cellular Biochemistry, College of Medicine, Ohio State University, Columbus, Ohio 43210

Mitochondrial superoxide () production is an important mediator of oxidative cellular injury. Succinate-cytochrome c reductase (SCR) of the electron transport chain has been implicated as an essential part of the mediation of generation and an alternative target of nitric oxide (NO) in the regulation of mitochondrial respiration. The Q cycle mechanism plays a central role in controlling both events. In the present work, generation by SCR was measured with the EPR spin-trapping technique using DEPMPO (5-diethoxylphosphoryl-5-methyl-1-pyrroline N-oxide) as the spin trap. In the presence of succinate, generation from SCR was detected as the spin adduct DEPMPO/·OOH. Inhibitors of the Q_o site only marginally reduced (20–30%) this production, suggesting a secondary role of in the mediation of generation. Addition of cyanide significantly decreased (70%) production, indicating the involvement of the heme component. UV-visible spectral analysis revealed that oxidation of ferrocytochrome b was accompanied by cytochrome c₁ reduction, and the reaction was mediated by the formation of an intermediate, indicating a direct role for cytochrome b in generation. In the presence of NO, DEPMPO/·OOH production was progressively diminished, implying that NO interacted with SCR or trapped the . The consumption of NO by SCR was investigated by electrochemical detection using an NO electrode. In the presence of succinate, SCR-mediated NO consumption was observed and inhibited by the addition of superoxide dismutase, suggesting the involvement of . Under the conditions of argon saturation, the NO consumption rate was not enhanced by succinate, suggesting a direct role for in the mediation of NO consumption. In the presence of succinate, oxidation of the ferrocytochrome b moiety of SCR was accelerated by the addition of NO, and was inhibited by argon saturation, indicating an indirect role for cytochrome b in the mediation of NO consumption.

Received for publication, December 21, 2005 , and in revised form, March 6, 2006.

^* This work was supported by National Institutes of Health Grants ES11031 and HL083237 (to Y.-R. C.) and HL63744, HL65608, and HL38324 (to J. L. Z.), and American Heart Association beginning Grant-in-aid 0365282B (to Y.-R. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 607 Davis Heart & Lung Research Institute, The Ohio State University, 473 W. 12th Ave., Columbus, OH 43210. Tel.: 614-688-4054; Fax: 614-292-8778; E-mail: yeong-renn.chen{at}osumc.edu.

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