The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2193/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 11, December 7, 1998 2193-2198

Brief Definitive Reports

A Caspase-activated Factor (CAF) Induces Mitochondrial Membrane Depolarization and Cytochrome c Release by a Nonproteolytic Mechanism

Margino Steemans, Vera Goossens, Marc Van de Craen, Franky Van Herreweghe, Katia Vancompernolle, Kurt De Vos, Peter Vandenabeele, and Johan Grooten

From the Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Gent, B-9000 Gent, Belgium

It is well established that apoptosis is accompanied by activation of procaspases and by mitochondrial changes, such as decrease in mitochondrial transmembrane potential ({Delta}{Psi}m) and release of cytochrome c. We analyzed the causal relationship between activated caspases and these mitochondrial phenomena. Purified recombinant caspase-1, -11, -3, -6, -7, and -8 were incubated with mitochondria in the presence or absence of additional cellular components, after which {Delta}{Psi}m was determined. At lower caspase concentrations, only caspase-8 was able to activate a cytosolic factor, termed caspase-activated factor (CAF), which resulted in decrease in {Delta}{Psi}m and release of cytochrome c. Both CAF-mediated activities could not be blocked by protease inhibitors, including oligopeptide caspase inhibitors. CAF-induced cytochrome c release, but not decrease of {Delta}{Psi}m, was blocked in mitochondria from cells overexpressing Bcl-2. CAF is apparently involved in decrease of {Delta}{Psi}m and release of cytochrome c, whereas Bcl-2 only prevents the latter. Hence, CAF may form the link between death domain receptor–dependent activation of procaspase-8 and the mitochondrial events studied.

Key Words: caspase • cytochrome c • mitochondria

Address correspondence to Johan Grooten, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Gent, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium. Phone: 32-9-264-53-10; Fax: 32-9-264-53-48; E-mail: johan.grooten{at}dmb.rug.ac.be

This research was supported by the Interuniversitaire Attractiepolen. M. Steemans and K. De Vos are fellows of the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-technologisch Onderzoek in de Industrie. K. Vancompernolle and P. Vandenabeele are postdoctoral researchers of the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen.


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