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J. Biol. Chem., Vol. 283, Issue 3, 1362-1371, January 18, 2008

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GTP Is Required for Iron-Sulfur Cluster Biogenesis in Mitochondria^*

Boominathan Amutha¹, Donna M. Gordon¹², Yajuan Gu, Elise R. Lyver, Andrew Dancis, and Debkumar Pain³

From the Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07101 and the Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Iron-sulfur (Fe-S) cluster biogenesis in mitochondria is an essential process and is conserved from yeast to humans. Several proteins with Fe-S cluster cofactors reside in mitochondria, including aconitase [4Fe-4S] and ferredoxin [2Fe-2S]. We found that mitochondria isolated from wild-type yeast contain a pool of apoaconitase and machinery capable of forming new clusters and inserting them into this endogenous apoprotein pool. These observations allowed us to develop assays to assess the role of nucleotides (GTP and ATP) in cluster biogenesis in mitochondria. We show that Fe-S cluster biogenesis in isolated mitochondria is enhanced by the addition of GTP and ATP. Hydrolysis of both GTP and ATP is necessary, and the addition of ATP cannot circumvent processes that require GTP hydrolysis. Both in vivo and in vitro experiments suggest that GTP must enter into the matrix to exert its effects on cluster biogenesis. Upon import into isolated mitochondria, purified apoferredoxin can also be used as a substrate by the Fe-S cluster machinery in a GTP-dependent manner. GTP is likely required for a common step involved in the cluster biogenesis of aconitase and ferredoxin. To our knowledge this is the first report demonstrating a role of GTP in mitochondrial Fe-S cluster biogenesis.

Received for publication, August 15, 2007 , and in revised form, November 19, 2007.

^* This work was supported by American Heart Association Grant 0655946T and a grant from the University of Medicine and Dentistry of New Jersey Foundation (to D. P.) and by National Institutes of Health Grant DK 53953 (to A. D.). 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 These authors contributed equally to this work.

² Present address: Dept. of Biological Sciences, Mississippi State University, MS 39762.

³ To whom correspondence should be addressed: Dept. of Pharmacology and Physiology, UMDNJ, NJ Medical School, 185 South Orange Ave., MSB I-669, Newark, NJ 07101-1709. Tel.: 973-972-3439; Fax: 973-972-7950; E-mail: painde{at}umdnj.edu.

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