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J. Biol. Chem., Vol. 279, Issue 9, 7785-7791, February 27, 2004

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Alternative Start Sites in the Saccharomyces cerevisiae GLR1 Gene Are Responsible for Mitochondrial and Cytosolic Isoforms of Glutathione Reductase^*

Caryn E. Outten and Valeria C. Culotta

From the Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205

To combat oxidative damage, eukaryotic cells have evolved with numerous anti-oxidant factors that are often distributed between cytosolic and mitochondrial pools. Glutathione reductase, which regenerates the reduced form of glutathione, represents one such anti-oxidant factor, yet nothing is known regarding the partitioning of this enzyme within the cell. Using the bakers' yeast Saccharomyces cerevisiae as a model, we provide evidence that a single gene, namely GLR1, encodes both the mitochondrial and cytosolic forms of glutathione reductase. A deletion in GLR1 drastically increases levels of oxidized glutathione in these two subcellular compartments. The GLR1 gene has two inframe start codons that are both used as translation initiation sites. Translation from the first codon generates the mitochondrial form that includes a mitochondrial targeting signal, whereas translation from the second codon produces the cytosolic form that lacks this sequence. Our results indicate that the sequence context of the two AUG codons influences the efficiency of translation initiation at each site, which in turn affects the relative levels of cytosolic and mitochondrial Glr1p. This method of subcellular distribution of glutathione reductase may be conserved in mammalian cells as well.

Received for publication, November 12, 2003

^* This work was supported by the Johns Hopkins University NIEHS Center and by the National Institutes of Health Grant GM 50016 (to V. C. C.). 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.

Supported by the National Institutes of Health Postdoctoral Fellowship GM 66594.

To whom correspondence should be addressed: Dept. of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe St., Rm. 7032, Baltimore, MD 21205. Tel.: 410-955-3029; Fax: 410-955-0116; E-mail: vculotta{at}jhsph.edu.

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