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J. Biol. Chem., Vol. 279, Issue 41, 42612-42618, October 8, 2004

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Cardiolipin Biosynthesis and Mitochondrial Respiratory Chain Function Are Interdependent^*

Vishal M. Gohil, Paulette Hayes, Shigemi Matsuyama, Hermann Schägger¶, Michael Schlame||, and Miriam L. Greenberg**

From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202, Blood Research Institute, The Blood Center of South Eastern Wisconsin and Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, ^¶Zentrum der Biologischen Chemie, Universitatsklinikum Frankfurt, D-60590 Frankfurt, Germany, and ^||Department of Anesthesiology, New York University, School of Medicine, New York, New York 10016

Cardiolipin (CL) is an acidic phospholipid present almost exclusively in membranes harboring respiratory chain complexes. We have previously shown that, in Saccharomyces cerevisiae, CL provides stability to respiratory chain supercomplexes and CL synthase enzyme activity is reduced in several respiratory complex assembly mutants. In the current study, we investigated the interdependence of the mitochondrial respiratory chain and CL biosynthesis. Pulse-labeling experiments showed that in vivo CL biosynthesis was reduced in respiratory complexes III (ubiquinol:cytochrome c oxidoreductase) and IV (cytochrome c oxidase) and oxidative phosphorylation complex V (ATP synthase) assembly mutants. CL synthesis was decreased in the presence of CCCP, an inhibitor of oxidative phosphorylation that reduces the pH gradient but not by valinomycin or oligomycin, both of which reduce the membrane potential and inhibit ATP synthase, respectively. The inhibitors had no effect on phosphatidylglycerol biosynthesis or CRD1 gene expression. These results are consistent with the hypothesis that in vivo CL biosynthesis is regulated at the level of CL synthase activity by the pH component of the proton-motive force generated by the functional electron transport chain. This is the first report of regulation of phospholipid biosynthesis by alteration of subcellular compartment pH.

Received for publication, March 5, 2004 , and in revised form, July 22, 2004.

^* This work was supported by Grant HL62263 from the National Institutes of Health (to M. L. G.), American Society of Hematology Junior Scholar Award (to S. M.), Northwestern Mutual Foundation research grant (to S. M.), American Heart Association grant-in-aid (to S. M.), and TAIHO Pharmaceutical Co. Ltd. (to S. M.). 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.

^** To whom correspondence should be addressed. Tel.: 313-577-5202; Fax: 313-577-6891; E-mail: MLGREEN{at}sun.science.wayne.edu.

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