Journal of Biological Chemistry
Volume 272, Issue 39, 26 September 1997, Pages 24154-24158
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CELL BIOLOGY AND METABOLISM
Direct Inhibition of Mitochondrial Respiratory Chain Complex III by Cell-permeable Ceramide*

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Ceramide is a lipid second messenger that mediates the effects of tumor necrosis factor α and other agents on cell growth and differentiation. Ceramide is believed to actvia activation of protein phosphatase, proline-directed protein kinase, or protein kinase C. Tumor necrosis factor α-induced common pathway of apoptosis is associated with an early impairment of mitochondria. Herein, we demonstrate that ceramide can directly inhibit mitochondrial respiratory chain function. In isolated mitochondria, a rapid decline of mitochondrial oxidative phosphorylation occurs in the presence of N-acetylsphingosine (C2-ceramide), a synthetic cell-permeable ceramide analog. An investigation of the site of ceramide action revealed that the activity of respiratory chain complex III is reduced by C2-ceramide with half-maximum effect at 5–7 μm. In contrast,N-acetylsphinganine (C2-dihydroceramide), which lacks a functionally critical double bond and is ineffective in cells, did not alter mitochondrial respiration or complex III activity. We suggest that these in vitro observations may set the stage for identifying a novel mechanism of regulation of mitochondrial function in vivo.

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*

This work was supported in part by National Institutes of Health Grants AG12447 and DK36069 and by funds from the Medical Research Service of the Department of Veterans Affairs.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.