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J. Biol. Chem., Vol. 283, Issue 16, 10252-10263, April 18, 2008

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Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation^*

Kimberly J. Aiken, Justin S. Bickford, Michael S. Kilberg, and Harry S. Nick^¶1

From the ^¶Department of Neuroscience, McKnight Brain Institute, Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging.

Received for publication, December 5, 2007

^* This work was supported by National Institutes of Health Grants HL39593 and HL06745 (to H. S. N.), DK52064, and DK70647 to (to M. S. K.). 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: Dept. of Neuroscience, P. O. Box 100244, College of Medicine, University of Florida, Gainesville, FL 32610. Tel.: 352-392-3303; Fax: 352-392-6511; E-mail: hnick{at}ufl.edu.

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