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J. Biol. Chem. 276 (41): 38061-38067

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Decreased Cardiolipin Synthesis Corresponds with Cytochrome c Release in Palmitate-induced Cardiomyocyte Apoptosis*

Darin B. OstranderDagger §, Genevieve C. SparagnaDagger §, Andrew A. Amoscato, Jeanie B. McMillinDagger , and William DowhanDagger **

From the Departments of Dagger  Biochemistry and Molecular Biology and Pathology and Laboratory Medicine, University of Texas-Houston, Medical School, Houston, Texas 77030 and the Mass Spectrometry Facility, University of Pittsburgh Center for Biotechnology and Bioengineering, Pittsburgh, Pennsylvania 15219 and the  Department of Pathology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213

Apoptosis has been identified recently as a component of many cardiac pathologies. However, the potential triggers of programmed cell death in the heart and the involvement of specific metabolic pathway(s) are less well characterized. Detachment of cytochrome c from the mitochondrial inner membrane is a necessary first step for cytochrome c release into the cytosol and initiation of apoptosis. The saturated long chain fatty acid, palmitate, induces apoptosis in rat neonatal cardiomyocytes and diminishes content of the mitochondrial anionic phospholipid, cardiolipin. These changes are accompanied by 1) acyl chain saturation of phosphatidic acid and phosphatidylglycerol, 2) large increases in the levels of these two phospholipids, and 3) a decline in cardiolipin synthesis. Although cardiolipin synthase activity is unchanged, saturated phosphatidylglycerol is a poor substrate for this enzyme. Under these conditions, decreased cardiolipin synthesis and release of cytochrome c are directly and significantly correlated. The results suggest that phosphatidylglycerol saturation and subsequent decreases in cardiolipin affect the association of cytochrome c with the inner mitochondrial membrane, directly influencing the pathway to cytochrome c release and subsequent apoptosis.

* This work was supported in part by National Institutes of Health Grants GM56389 (to W. D.) and 5P30CA47904-12 (to A. A. A), American Heart Association Grant 9950584N (to J. B. M.), and NHLBI National Institutes of Health Grants HL10304 (to D. B. O.) and HL10019 (to G. C. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

** To whom correspondence should be addressed. Tel.: 713-500-6051; Fax: 713-500-0652; E-mail: william.dowhan@uth.tmc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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