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J. Biol. Chem., Vol. 283, Issue 12, 7554-7560, March 21, 2008

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F1000 Biology *Must Read* - FREE!

Functional Mitochondria Are Required for -Synuclein Toxicity in Aging Yeast^*

Sabrina Büttner, Alessandro Bitto, Julia Ring, Manuela Augsten, Piotr Zabrocki¹, Tobias Eisenberg, Helmut Jungwirth, Sylvia Hutter, Didac Carmona-Gutierrez, Guido Kroemer^¶||**, Joris Winderickx²³, and Frank Madeo²⁴

From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, Functional Biology, Catholic University of Leuven, B-3000 Leuven, Belgium, ^¶INSERM, U848, 94805 Villejuif, France, the ^||Institut Gustave Roussy, 94805 Villejuif, France, and the ^**University Paris-Sud, Paris 11, 94805 Villejuif, France

-Synuclein is one of the principal toxic triggers of Parkinson disease, an age-associated neurodegeneration. Using old yeast as a model of -synuclein expression in post-mitotic cells, we show that -synuclein toxicity depends on chronological aging and results in apoptosis as well as necrosis. Neither disruption of key components of the unfolded protein response nor deletion of proapoptotic key players (including the yeast caspase YCA1, the apoptosis-inducing factor AIF1, or the serine protease OMI) did prevent -synuclein-induced cell killing. However, abrogation of mitochondrial DNA (rho⁰) inhibited -synuclein-induced reactive oxygen species formation and subsequent apoptotic cell death. Thus, introducing an aging yeast model of -synuclein toxicity, we demonstrate a strict requirement of functional mitochondria.

Received for publication, October 11, 2007 , and in revised form, December 31, 2007.

^* This work was supported in part by grants from the Fonds zur Förderung der wissenschaftlichen Forschung (Austria) (Grant S-9304-B05) (to F. M., S. B., and D. C.-G.), Deutsche Forschungsgemeinschaft (Germany) (Grant MA2587) (to F. M. and T. E.). 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 a supplemental figure.

¹ Supported by a European Community Marie Curie fellowship (MEIF-CT-2005-514281) and supported by the Marie Curie Ph.D. Graduate School Neurodegeneration in Alzheimer's Disease (NEURAD).

² Both authors share equally contributing senior authorship.

³ Supported by the Fund for Scientific Research-Flanders (Fonds Weten-schappelijk Onderzoek-Vlaanderen), the KULeuven Research Fund (KULeuven-BOF), and the KULeuven R&D. To whom correspondence may be addressed: K.U. Leuven, Kasteelpark Arenberg 31, B-3001 Heverlee, Belgium. Fax: 32-16-321967; E-mail: joris.winderickx{at}bio.kuleuven.be. ⁴To whom correspondence may be addressed: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria. Fax: 43-316-3809898; E-mail: frank.madeo{at}uni-graz.at.

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