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J. Biol. Chem., Vol. 281, Issue 35, 25757-25767, September 1, 2006

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Crucial Mitochondrial Impairment upon CDC48 Mutation in Apoptotic Yeast^*

Ralf J. Braun¹, Hans Zischka¹², Frank Madeo^¶, Tobias Eisenberg^¶, Silke Wissing^||, Sabrina Büttner^¶, Silvia M. Engelhardt^||, Dietmute Büringer^**, and Marius Ueffing

From the GSF-National Research Center for Environment and Health, Institute of Human Genetics, Ingolstaedter Landstrasse 1, Munich-Neuherberg D-85764, Germany, the GSF-National Research Center for Environment and Health, Institute of Toxicology, Munich-Neuherberg D-85764, Germany, the ^¶University of Graz, Institute of Molecular Biosciences, Graz A-8010, Austria, the ^||University of Tübingen, Institute for Physiological Chemistry, Tübingen D-72076, Germany, the ^**Max Planck Institute for Neurobiology, Department of Systems and Computational Neurobiology, Martinsried D-82152, Germany, and the Technical University Munich, Institute of Human Genetics, Klinikum rechts der Isar, Munich D-81675, Germany

Mutation in CDC48 (cdc48^S565G), a gene essential in the endo-plasmic reticulum (ER)-associated protein degradation (ERAD) pathway, led to the discovery of apoptosis as a mechanism of cell death in the unicellular organism Saccharomyces cerevisiae. Elucidating Cdc48p-mediated apoptosis in yeast is of particular interest, because Cdc48p is the highly conserved yeast orthologue of human valosin-containing protein (VCP), a pathological effector for polyglutamine disorders and myopathies. Here we show distinct proteomic alterations in mitochondria in the cdc48^S565G yeast strain. These observed molecular alterations can be related to functional impairment of these organelles as suggested by respiratory deficiency of cdc48^S565G cells. Mitochondrial dysfunction in the cdc48^S565G strain is accompanied by structural damage of mitochondria indicated by the accumulation of cytochrome c in the cytosol and mitochondrial enlargement. We demonstrate accumulation of reactive oxygen species produced predominantly by the cytochrome bc₁ complex of the mitochondrial respiratory chain as suggested by the use of inhibitors of this complex. Concomitantly, emergence of caspase-like enzymatic activity occurs suggesting a role for caspases in the cell death process. These data strongly point for the first time to a mitochondrial involvement in Cdc48p/VCP-dependent apoptosis.

Received for publication, December 23, 2005 , and in revised form, April 6, 2006.

^* This work was supported by the German Federal Ministry for Education and Research (Grant FKZ 031U108E, subproject B3 to H. Z., R. J. B., and M. U.), NGFN2 SMP Proteomics (Grant FKZ 01GR0449, subproject 9 to R. J. B. and M. U.), the European Union EU-IP "Interaction Proteome" (Grant LSHG-CT-2003-505520 to R. J. B. and M. U.), the Deutsche Forschungsgemeinschaft (to F. M., S. M. E., and S. W.), and the Austrian "Fonds zur Förderung der wissenschaftlichen Forschung" Project (Grant S9304-B05 to F. M., T. E., and S. B.) The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49(0)89-3187-2663; Fax: 49(0)89-3187-3449; E-mail: zischka{at}gsf.de.

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