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Originally published In Press as doi:10.1074/jbc.M007198200 on October 16, 2000

J. Biol. Chem., Vol. 276, Issue 2, 1503-1509, January 12, 2001
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Adrenodoxin Reductase Homolog (Arh1p) of Yeast Mitochondria Required for Iron Homeostasis*

Jie LiDagger , Sandeep Saxena§, Debkumar Pain§, and Andrew DancisDagger

From the Dagger  Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the § Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Arh1p is an essential mitochondrial protein of yeast with reductase activity. Here we show that this protein is involved in iron metabolism. A yeast strain was constructed in which the open reading frame was placed under the control of a galactose-regulated promoter. Protein expression was induced by galactose and repressed to undetectable levels in the absence of galactose, although cells grew quite well in the absence of inducer. Under noninducing conditions, cellular iron uptake was dysregulated, exhibiting a failure to repress in response to medium iron. Iron trafficking within the cell was also disturbed. Exposure of Arh1p-depleted cells to increasing iron concentrations during growth led to drastic increases in mitochondrial iron, indicating a loss of homeostatic control. Activity of aconitase, a prototype Fe-S protein, was deficient at all concentrations of mitochondrial iron, although the protein level was unaltered. Heme protein deficiencies were exacerbated in the iron-loaded mitochondria, suggesting a toxic side effect of accumulated iron. Finally, a time course correlated the cellular depletion of Arh1p with the coordinated appearance of various mutant phenotypes including dysregulated cellular iron uptake, deficiency of Fe-S protein activities in mitochondria and cytoplasm, and deficiency of hemoproteins. Thus, Arh1p is required for control of cellular and mitochondrial iron levels and for the activities of Fe-S cluster proteins.

* This work was supported in part by National Institutes of Health Grant GM57067 and American Heart Association Grant 9951300U (to D. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported in part by National Institutes of Health Grant DK53953. To whom correspondence should be addressed. Tel.: 215-573-6275; Fax: 215-573-7049; E-mail: adancis@mail.med.upenn.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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