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J. Biol. Chem., Vol. 283, Issue 19, 12681-12685, May 9, 2008

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Mitochondrial Protein Quality Control by the Proteasome Involves Ubiquitination and the Protease Omi^*

Susanne Radke, Harish Chander, Patrick Schäfer, Gregor Meiss, Rejko Krüger^¶1, Jörg B. Schulz^||12, and Doris Germain³

From the Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, New York 10029, the Institute of Biochemistry, Justus-Liebig-University, Heinrich-Buff-Ring 58, D-35392 Giessen, Germany, the ^¶Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076, Tübingen, Germany and the ^||Centers of Molecular Physiology of the Brain and Medical Neurology, University of Göttingen, Waldweg 33, D-37073 Göttingen, Germany

We report here that blocking the activity of the 26 S proteasome results in drastic changes in the morphology of the mitochondria and accumulation of intermembrane space (IMS) proteins. Using endonuclease G (endoG) as a model IMS protein, we found that accumulation of wild-type but to a greater extent mutant endoG leads to changes in the morphology of the mitochondria similar to those observed following proteasomal inhibition. Further, we show that wild-type but to a greater extent mutant endoG is a substrate for ubiquitination, suggesting the presence of a protein quality control. Conversely, we also report that wild-type but not mutant endoG is a substrate for the mitochondrial protease Omi but only upon inhibition of the proteasome. These findings suggest that although elimination of mutant IMS proteins is strictly dependent on ubiquitination, elimination of excess or spontaneously misfolded wild-type IMS proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient. One implication of our finding is that in the context of attenuated proteasomal function, accumulation of IMS proteins would contribute to the collapse of the mitochondrial network such as that observed in neurodegenerative diseases. Another implication is that such collapse could be accelerated either by mutations in IMS proteins or by mutations in Omi itself.

Received for publication, February 20, 2008 , and in revised form, March 17, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health RO1 Grant CA109482 (to D. G.). This work was also supported by the Samuel Waxman Cancer Research Foundation. 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 five supplemental figures.

¹ Supported by Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie funds (Grant NGFN2).

² Supported by the Deutsche Forschungsgemeinschaft research center "Molecular Physiology of the Brain."

³ To whom correspondence should be addressed: Gustave L. Levy Place, Box 1178 New York, 10029. Tel.: 212-241-9541; Fax: 212-996-5787; E-mail: doris.germain{at}mssm.edu.