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J. Biol. Chem., Vol. 280, Issue 8, 6701-6708, February 25, 2005

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Friedreich's Ataxia, No Changes in Mitochondrial Labile Iron in Human Lymphoblasts and Fibroblasts

A DECREASE IN ANTIOXIDATIVE CAPACITY?^*

Brigitte Sturm, Ute Bistrich, Matthias Schranzhofer¶, Joseph P. Sarsero||, Ursula Rauen, Barbara Scheiber-Mojdehkar, Herbert de Groot, Panos Ioannou||, and Frank Petrat**

From the Department of Medical Chemistry, Medical University of Vienna, Waehringerstrasse 10, 1090 Vienna, Austria, the Institut für Physiologische Chemie, Universitätsklinikum, D-45122 Essen, Germany, the ^¶Division of Molecular Biology, Institute of Medical Biochemistry, Max F. Perutz Laboratories, The Vienna Biocenter, Dr. Bohr-Gasse 7-9, 1030 Vienna, Austria, and the ^||Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia

Friedreich's ataxia (FRDA) is caused by low expression of frataxin, a small mitochondrial protein. Studies with both yeast and mammals have suggested that decreased frataxin levels lead to elevated intramitochondrial concentrations of labile (chelatable) iron, and consequently to oxidative mitochondrial damage. Here, we used the mitochondrion-selective fluorescent iron indicator/chelator rhodamine B-[(1,10-phenanthrolin-5-yl)aminocarbonyl]benzylester (RPA) to determine the mitochondrial chelatable iron of FRDA patient lymphoblast and fibroblast cell lines, in comparison with age- and sex-matched control cells. No alteration in the concentration of mitochondrial chelatable iron could be observed in patient cells, despite strongly decreased frataxin levels. Uptake studies with ⁵⁵Fe-transferrin and iron loading with ferric ammonium citrate revealed no significant differences in transferrin receptor density and iron responsive protein/iron regulatory element binding activity between patients and controls. However, sensitivity to H₂O₂ was significantly increased in patient cells, and H₂O₂ toxicity could be completely inhibited by the ubiquitously distributing iron chelator 2,2'-dipyridyl, but not by the mitochondrion-selective chelator RPA. Our data strongly suggest that frataxin deficiency does not affect the mitochondrial labile iron pool or other parameters of cellular iron metabolism and suggest a decreased antioxidative defense against extramitochondrial iron-derived radicals in patient cells. These results challenge current concepts favoring the use of mitochondrion-specific iron chelators and antioxidants to treat FRDA.

Received for publication, July 30, 2004 , and in revised form, December 17, 2004.

^* This work was supported in part by the Austrian Research Foundation (FWF P147842-PAT) and by the Hochschuljubiläumsstiftung der Stadt Wien (1141/2002) (to B. S.) and by an IFORES grant of the University of Duisburg-Essen (to U. B.). The work at the Murdoch Children's Research Institute was supported by the National Ataxia Foundation and the Bethlehem Griffiths Research Foundation. 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: Institut für Physiologische Chemie, Universitätsklinikum, Hufelandstr. 55, D-45122 Essen, Germany. Tel.: 49-201-723-4105; Fax: 49-201-723-5943; E-mail: frank.petrat{at}uni-essen.de.

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