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Molecular and Cellular Biology, May 1999, p. 3299-3311, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Uncouplers of Oxidative Phosphorylation Can Enhance a Fas Death Signal

Georg Linsinger, Sabine Wilhelm, Hermann Wagner, and Georg Häcker*

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany

Received 17 November 1998/Accepted 21 January 1999

Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential Delta Psi m. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2,4-dinitrophenol (DNP) reduce Delta Psi m by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis.

* Corresponding author. Mailing address: Institute for Medical Microbiology, Technische Universität München, Trogerstr. 9, 81675 Munich, Germany. Phone: 49-89-4140-4120. Fax: 49-89-4140-4868. E-mail: hacker{at}lrz.tu-muenchen.de.

Molecular and Cellular Biology, May 1999, p. 3299-3311, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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