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Originally published In Press as doi:10.1074/jbc.M004239200 on July 5, 2000

J. Biol. Chem., Vol. 275, Issue 38, 29187-29192, September 22, 2000
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Yeast Lacking Superoxide Dismutase(s) Show Elevated Levels of "Free Iron" as Measured by Whole Cell Electron Paramagnetic Resonance*

Chandra SrinivasanDagger , Amir LibaDagger , James A. Imlay§, Joan Selverstone ValentineDagger , and Edith Butler GrallaDagger

From the Dagger  Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569 and the § Department of Microbiology, University of Illinois, Urbana, Illinois 61801

A current hypothesis explaining the toxicity of superoxide anion in vivo is that it oxidizes exposed [4Fe-4S] clusters in certain vulnerable enzymes causing release of iron and enzyme inactivation. The resulting increased levels of "free iron" catalyze deleterious oxidative reactions in the cell. In this study, we used low temperature Fe(III) electron paramagnetic resonance (EPR) spectroscopy to monitor iron status in whole cells of the unicellular eukaryote, Saccharomyces cerevisiae. The experimental protocol involved treatment of the cells with desferrioxamine, a cell-permeant, Fe(III)-specific chelator, to promote oxidation of all of the "free iron" to the Fe(III) state wherein it is EPR-detectable. Using this method, a small amount of EPR-detectable iron was detected in the wild-type strain, whereas significantly elevated levels were found in strains lacking CuZn-superoxide dismutase (CuZn-SOD) (sod1Delta ), Mn-SOD (sod2Delta ), or both SODs, throughout their growth but particularly in stationary phase. The accumulation was suppressed by expression of wild-type human CuZn-SOD (in the sod1Delta mutant), by pmr1, a genetic suppressor of the sodDelta mutant phenotype (in the sod1Delta sod2Delta double knockout strain), and by anaerobic growth. In wild-type cells, an increase in the EPR-detectable iron pool could be induced by treatment with paraquat, a redox-cycling drug that generates superoxide. Cells that were not pretreated with desferrioxamine had Fe(III) EPR signals that were equally as strong as those from treated cells, indicating that "free iron" accumulated in the ferric form in our strains in vivo. Our results indicate a relationship between superoxide stress and iron handling and support the above hypothesis for superoxide-related oxidative damage.

* This work was supported by National Institutes of Health Grants DK46828 (to J. S. V.) and GM59030 (to J. A. I.).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.

To whom correspondence should be addressed. Tel.: 310-825-1946; Fax: 310-206-7197; E-mail: egralla@chem.ucla.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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