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J. Biol. Chem., Vol. 281, Issue 32, 22493-22502, August 11, 2006

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Mrs3p, Mrs4p, and Frataxin Provide Iron for Fe-S Cluster Synthesis in Mitochondria^*

Yan Zhang, Elise R. Lyver, Simon A. B. Knight, Debkumar Pain, Emmanuel Lesuisse^¶, and Andrew Dancis¹

From the Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the Department of Pharmacology and Physiology, The University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07101, and ^¶Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Département de Biologie des Génomes, Institut Jacques Monod, Unité Mixte de Recherche 7592 CNRS-Universites Paris 6 and 7, 2 Place Jussieu, F-75251 Paris Cedex 05, France

Yeast Mrs3p and Mrs4p are evolutionarily conserved mitochondrial carrier proteins that transport iron into mitochondria under some conditions. Yeast frataxin (Yfh1p), the homolog of the human protein implicated in Friedreich ataxia, is involved in iron homeostasis. However, its precise functions are controversial. Anaerobically grown triple mutant cells (mrs3/4/yfh1) displayed a severe growth defect corrected by in vivo iron supplementation. Because anaerobically grown cells do not synthesize heme, and they do not experience oxidative stress, this growth defect was most likely due to Fe-S cluster deficiency. Fe-S cluster formation was assessed in anaerobically grown cells shifted to air for a brief period. In isolated mitochondria, Fe-S clusters were detected on newly imported yeast ferredoxin precursor and on endogenous aconitase by means of [³⁵S]cysteine labeling and native gel separation. New cluster formation was dependent on iron addition to mitochondria, and the iron concentration dependence was shifted dramatically upward in the mrs3/4 mutant, indicating a role of Mrs3/4p in iron transport. The frataxin mutant strain lacked protein import capacity because of low mitochondrial membrane potential, although this was partially restored by growth in the presence of high iron. Under these conditions, a kinetic defect in new Fe-S cluster formation was still noted. Import of frataxin into frataxin-minus isolated mitochondria promptly corrected the Fe-S cluster assembly defect without further iron addition. These findings show that Mrs3/4p transports iron into mitochondria, whereas frataxin makes iron already within mitochondria available for Fe-S cluster synthesis.

Received for publication, May 3, 2006 , and in revised form, June 5, 2006.

^* This work was supported by National Institutes of Health Grant DK43953 (to A. D.) and American Heart Association Grant 03557107 (to D. P.). 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.

¹ To whom correspondence should be addressed. Tel.: 215-573-6275; Fax: 215-573-7049; E-mail: adancis{at}mail.med.upenn.edu.

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