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J. Biol. Chem., Vol. 282, Issue 34, 24842-24850, August 24, 2007

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Cytotoxic Phospholipid Oxidation Products

CELL DEATH FROM MITOCHONDRIAL DAMAGE AND THE INTRINSIC CASPASE CASCADE^*

From the Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195

Phospholipid oxidation products accumulate in the necrotic core of atherosclerotic lesions, in apoptotic cells, and circulate in oxidized low density lipoprotein. Phospholipid oxidation generates toxic products, but little is known about which specific products are cytotoxic, their receptors, or the mechanism(s) that induces cell death. We find the most common phospholipid oxidation product of oxidized low density lipoprotein, phosphatidylcholine with esterified sn-2-azelaic acid, induced apoptosis at low micromolar concentrations. The synthetic ether phospholipid hexadecyl azelaoyl phosphatidylcholine (HAzPC) was rapidly internalized, and overexpression of PLA2g7 (PAF acetylhydrolase) that specifically hydrolyzes such oxidized phospholipids suppressed apoptosis. Internalized HAzPC associated with mitochondria, and cytochrome c, and apoptosis-inducing factor escaped from mitochondria to the cytoplasm and nucleus, respectively, in cells exposed to HAzPC. Isolated mitochondria exposed to HAzPC rapidly swelled and released cytochrome c and apoptosis-inducing factor. Other phospholipid oxidation products induced swelling, but HAzPC was the most effective and was twice as effective as its diacyl homolog. Cytoplasmic cytochrome c completes the apoptosome, and activated caspase 9 and 3 were present in cells exposed to HAzPC. Irreversible inhibition of caspase 9 blocked downstream caspase 3 activation and prevented apoptosis. Mitochondrial damage initiated this apoptotic cascade, because overexpression of Bcl-X_L, an anti-apoptotic protein localized to mitochondria, blocked cytochrome c escape and apoptosis. Thus, exogenous phospholipid oxidation products target intracellular mitochondria to activate the intrinsic apoptotic cascade.

Received for publication, April 4, 2007 , and in revised form, June 14, 2007.

^* This work was supported by Grant HL44513 from the National Institutes of Health (to T. M. M.). The work was made possible through the services offered by the mass spectrometry core II, the electron microscopy imaging core, as well as the flow cytometry core, the imaging core, and the media preparation core facilities of the Cleveland Clinic. 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: Dept. of Cell Biology, NE10, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-1048; Fax: 216-444-9404; E-mail: mcintyt{at}ccf.org.

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