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J Biol Chem, Vol. 274, Issue 10, 6080-6084, March 5, 1999

Ceramide Induces Cytochrome c Release from Isolated Mitochondria
IMPORTANCE OF MITOCHONDRIAL REDOX STATE

From the Laboratory of Biochemistry I, Swiss Federal Institute of Technology, Universitatsstrasse 16 and the ^¶ Department of Radiation Oncology, University Hospital of Zurich, CH-8092 Zurich, Switzerland

In the present study we show that N-acetylsphingosine (C₂-ceramide), N-hexanoylsphingosine (C₆-ceramide), and, to a much lesser extent, C₂-dihydroceramide induce cytochrome c (cyto c) release from isolated rat liver mitochondria. Ceramide-induced cyto c release is prevented by preincubation of mitochondria with a low concentration (40 nM) of Bcl-2. The release takes place when cyto c is oxidized but not when it is reduced. Upon cyto c loss, mitochondrial oxygen consumption, mitochondrial transmembrane potential (), and Ca²⁺ retention are diminished. Incubation with Bcl-2 prevents, and addition of cyto c reverses the alteration of these mitochondrial functions. In ATP-energized mitochondria, ceramides do not alter , neither when cyto c is oxidized nor when it is reduced, ruling out a nonspecific disturbance by ceramides of mitochondrial membrane integrity. Furthermore, ceramides decrease the reducibility of cyto c. We conclude that the apoptogenic properties of ceramides are in part mediated via their interaction with mitochondrial cyto c followed by its release and that the redox state of cyto c influences its detachment by ceramide from the inner mitochondrial membrane.

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