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J. Biol. Chem., Vol. 278, Issue 48, 47365-47369, November 28, 2003

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Compartment-specific Protection of Iron-Sulfur Proteins by Superoxide Dismutase^*

Fanis Missirlis, Jianguo Hu, Kim Kirby, Arthur J. Hilliker¶, Tracey A. Rouault, and John P. Phillips||

From the Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, the Department of Molecular Biology and Genetics, University of Guelph, Guelph, Ontario N1G 2W1, Canada and the ^¶Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada

Iron and oxygen are essential but potentially toxic constituents of most organisms, and their transport is meticulously regulated both at the cellular and systemic levels. Compartmentalization may be a homeostatic mechanism for isolating these biological reactants in cells. To investigate this hypothesis, we have undertaken a genetic analysis of the interaction between iron and oxygen metabolism in Drosophila. We show that Drosophila iron regulatory protein-1 (IRP1) registers cytosolic iron and oxidative stress through its labile iron sulfur cluster by switching between cytosolic aconitase and RNA-binding functions. IRP1 is strongly activated by silencing and genetic mutation of the cytosolic superoxide dismutase (Sod1), but is unaffected by silencing of mitochondrial Sod2. Conversely, mitochondrial aconitase activity is relatively insensitive to loss of Sod1 function, but drops dramatically if Sod2 activity is impaired. This strongly suggests that the mitochondrial boundary limits the range of superoxide reactivity in vivo. We also find that exposure of adults to paraquat converts cytosolic aconitase to IRP1 but has no affect on mitochondrial aconitase, indicating that paraquat generates superoxide in the cytosol but not in mitochondria. Accordingly, we find that transgene-mediated overexpression of Sod2 neither enhances paraquat resistance in Sod1⁺ flies nor compensates for lack of SOD1 activity in Sod1-null mutants. We conclude that in vivo, superoxide is confined to the subcellular compartment in which it is formed, and that the mitochondrial and cytosolic SODs provide independent protection to compartment-specific protein iron-sulfur clusters against attack by superoxide generated under oxidative stress within those compartments.

Received for publication, July 16, 2003 , and in revised form, September 10, 2003.

^* This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC) (to J. P. P. and A. J. H.) and by the Intramural program of the National Institute of Child Health and Human Development (NICHD). 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.: 519-824-4120 (ext. 52796); Fax: 519-837-2075; E-mail: jphillip{at}uoguelph.ca.

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