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J. Biol. Chem., Vol. 280, Issue 6, 4207-4212, February 11, 2005

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Down-regulation of Iron Regulatory Protein 1 Activities and Expression in Superoxide Dismutase 1 Knock-out Mice Is Not Associated with Alterations in Iron Metabolism^*

Rafa R. Starzyski, Pawe Lipiski, Jean-Claude Drapier¶, Alexandre Diet¶, Ewa Smuda, Teresa Bartomiejczyk||, Mikoaj A. Gralak**, and Marcin Kruszewski||

From the Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzêbiec, 05-552 Wólka Kosowska, Poland, the ^¶Institut de Chimie des Substances Naturelles, CNRS, 91190 Gif-sur-Yvette, France, the ^||Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology, 03-195 Warszawa, ul. Dorodna 16, Poland, and the ^**Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw Agricultural University, Nowoursynowska 159, 02-776 Warszawa, Poland

Iron and oxygen (O₂) are intimately associated in many well characterized patho-physiological processes. These include oxidation of the [4Fe-4S] cluster of mitochondrial aconitase and inactivation of this Krebs cycle enzyme by the superoxide anion (), a product of the one-electron of reduction O₂. In contrast to the apparent toxicity of this reaction, the biological consequences of -mediated inactivation of the cytosolic counterpart of mitochondrial aconitase, commonly known as iron regulatory protein 1 (IRP1), are not clear. Apart from its ability to convert citrate to iso-citrate, IRP1 in its apo-form binds to iron-responsive elements in the untranslated regions of mRNAs coding for proteins involved in iron metabolism, to regulate their synthesis and thus control the cellular homeostasis of this metal. Here, we show that in superoxide dismutase 1 (SOD1) knock-out mice, lacking Cu,Zn-SOD, an enzyme that acts to reduce the concentration of mainly in cytosol, not only is aconitase activity of IRP1 inhibited but the level of IRP1 is also strongly decreased. Despite such an evident alteration in IRP1 status, SOD1-deficient mice display a normal iron metabolism phenotype. Our findings clearly show that under conditions of -mediated oxidative stress, IRP1 is not essential for the maintenance of iron metabolism in mammals.

Received for publication, September 27, 2004 , and in revised form, November 10, 2004.

^* This work was supported by NATO Collaborative Linkage Grant SEA(LST.CLG.979519), the State Committee for Scientific Research Statutory grant for Institut of Nuclear Chemistry and Technology, and the Centre National de la Recherche Scientifique, France (CNRS-Polish Academy of Sciences agreement). 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.: 48-22-7561711; Fax: 48-22-7561417; E-mail: P.Lipinski{at}ighz.pl.

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