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Originally published In Press as doi:10.1074/jbc.M200754200 on May 10, 2002

J. Biol. Chem., Vol. 277, Issue 30, 26796-26803, July 26, 2002
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Ceramide Channels Increase the Permeability of the Mitochondrial Outer Membrane to Small Proteins*

Leah J. SiskindDagger §, Richard N. Kolesnick, and Marco ColombiniDagger ||

From the Dagger  Department of Biology, University of Maryland, College Park, Maryland 20742 and the  Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Ceramides are known to play a major regulatory role in apoptosis by inducing cytochrome c release from mitochondria. We have previously reported that C2- and C16-ceramide, but not dihydroceramide, form large channels in planar membranes (Siskind, L. J., and Colombini, M. (2001) J. Biol. Chem. 275, 38640-38644). Here we show that ceramides do not trigger a cytochrome c secretion or release mechanism, but simply raise the permeability of the mitochondrial outer membrane, via ceramide channel formation, to include small proteins. Exogenously added reduced cytochrome c was able to freely permeate the mitochondrial outer membrane with entry to and exit from the intermembrane space facilitated by ceramides in a dose- and time-dependent manner. The permeability pathways were eliminated upon removal of C2-ceramide by bovine serum albumin, thus ruling out a detergent-like effect of C2-ceramide on membranes. Ceramide channels were not specific to cytochrome c, as ceramides induced release of adenylate kinase, but not fumerase from isolated mitochondria, showing some specificity of these channels for the outer mitochondrial membrane. SDS-PAGE results show that ceramides allow release of intermembrane space proteins with a molecular weight cut-off of about 60,000. These results indicate that the ceramide-induced membrane permeability increases in isolated mitochondria are via ceramide channel formation and not a release mechanism, as the channels that allow cytochrome c to freely permeate are reversible, and are not specific to cytochrome c.

* 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.

§ Supported by a National Research Service Award (NRSA) National Institutes of Health predoctoral fellowship.

|| To whom correspondence and reprint requests should be addressed. Tel.: 301-405-6925; Fax: 301-314-9358; E-mail: mc34@umail.umd.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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