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Department of Microbiology, North Carolina State University, Raleigh, NC 27695
Apoptosis is often accompanied by activation of phospholipase A2, causing release of free fatty acids (FFAs), which in turn are thought to contribute to the loss of mitochondrial transmembrane potential (
m). In these experiments, we asked whether calcium plays a role as an intermediate in this process. A total of 14 FFAs were compared for their ability to cause loss of m and for their ability to affect levels of intracellular calcium. Among the FFAs, unsaturated FFAs tended to induce apoptosis while saturated FFAs did not. Arachidonic acid (AA) was most damaging, causing loss of m and cell death in 8–10 h while linoleic acid, 
-linolenic acid, and docosapentaenoic also strongly induced apoptosis. Effects of the FFAs on levels of intracellular calcium were very different. Many caused strong calcium responses; however, the ability to induce a strong calcium response was not predictive of ability to induce apoptosis, and overall, we did not find a correlation between apoptosis and calcium induction. Also, verapamil and TMB-8 were able to block the calcium response, but these inhibitors did not prevent loss of m, indicating that the calcium response is not necessary for FFA-induced loss of m. In contrast, we found that cyclosporine A could inhibit the AA-induced loss of m with both whole cells and isolated mitochondria, confirming that the antimitochondrial effects of FFA can stem from direct effects on the mitochondrial permeability transition pore. Finally, we show that the strong apoptosis-inducing activity of AA may stem from its ability to selectively induce its own release.
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 This work was supported by Grant CA-59032 from the National Institutes of Health and Project No. 06333 from the North Carolina Agricultural Research Service.
2 Address correspondence and reprint requests to Dr. Scott M. Laster, Department of Microbiology, North Carolina State University, Raleigh, NC 27695. E-mail address: scott_laster{at}ncsu.edu
3 Abbreviations used in this paper: PLA2, phospholipase A2; cPLA2, cytosolic PLA2; FA, fatty acid; FFA; free FA; AA, arachidonic acid; MPTP, mitochondrial permeability transition pore; 
m, mitochondrial transmembrane potential; CSA, cyclosporine A; MYA, myristic acid; PA, palmitic acid; SA, stearic acid; AIA, arachidic acid; POA, palmitoleic acid; OA, oleic acid; LA, linoleic acid; EDA, eicosadienoic acid; GLA, -linolenic acid; MA, mead acid; EPA, eicosapentaenoic acid; DPA, docosapentaenoic acid; DHA, docosahexaenoic acid; TMB-8, 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester.
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