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J. Biol. Chem., Vol. 280, Issue 20, 19794-19807, May 20, 2005

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Frataxin and Mitochondrial Carrier Proteins, Mrs3p and Mrs4p, Cooperate in Providing Iron for Heme Synthesis^*

Yan Zhang, Elise R. Lyver, Simon A. B. Knight, Emmanuel Lesuisse, and Andrew Dancis¶

From the Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Département de Biologie des Génomes, Institut Jacques Monod, Unité Mixte de Recherche 7592 CNRS-Universités Paris 6 and 7, 2 Place Jussieu, F-75251 Paris cedex 05, France

Frataxin is a conserved mitochondrial protein implicated in cellular iron metabolism. Deletion of the yeast frataxin homolog (YFH1) was combined with deletions of MRS3 and MRS4, mitochondrial carrier proteins implicated in iron homeostasis. As previously reported, the yfh1 mutant accumulated iron in mitochondria, whereas the triple mutant () did not. When wild-type, mrs3/4, yfh1, and strains were incubated anaerobically, all strains were devoid of heme and protected from iron and oxygen toxicity. The cultures were then shifted to air for a short time (4–5 h) or a longer time (15 h), and the evolving mutant phenotypes were analyzed (heme-dependent growth, total heme, cytochromes, heme proteins, and iron levels). A picture emerges from these data of defective heme formation in the mutants, with a markedly more severe defect in the than in the individual mrs3/4 or yfh1 mutants (a "synthetic" defect in the genetic sense). The defect(s) in heme formation could be traced to lack of iron. Using a real time assay of heme biosynthesis, porphyrin precursor and iron were presented to permeabilized cells, and the appearance and disappearance of fluorescent porphyrins were followed. The Mrs3/4p carriers were required for rapid iron transport into mitochondria for heme synthesis, whereas there was also evidence for an alternative slower system. A different role for Yfh1p was observed under conditions of low mitochondrial iron and aerobic growth (revealed in the ), acting to protect bioavailable iron within mitochondria and to facilitate its use for heme synthesis.

Received for publication, January 12, 2005 , and in revised form, March 10, 2005.

^* This work was supported by National Institutes of Health Grant DK53953 (to A. D.) and Association pour la Recherche sur le Cancer Grant ARC 5439 (to E. L.). 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.

^¶ 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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