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Human Molecular Genetics Advance Access published online on June 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm163
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Frataxin is essential for extramitochondrial Fe-S cluster proteins in mammalian tissues

Alain Martelli{dagger},1,2,3,4,5, Marie Wattenhofer-Donzé{dagger},1,2,3,4,5, Stéphane Schmucker1,2,3,4,5, Samuel Bouvet1,2,3,4,5, Laurence Reutenauer1,2,3,4,5 and Hélène Puccio*,1,2,3,4,5

1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 1 rue Laurent Fries BP 10142, Illkirch, F-67400 France 2 Inserm, U596, Illkirch, F-67400 France 3 CNRS, UMR7104, Illkirch, F-67400 France 4 Université Louis Pasteur, Strasbourg, F-67000 France 5 Collège de France, Chaire de génétique humaine, Illkirch, F-67400 France

* To whom correspondence should be addressed: Tel: 33-3-88-65-32-64; Fax: 33-3-88-65-32-46; E-mail: hpuccio{at}titus.igbmc.u-strasbg.fr

Received May 28, 2007; Revised June 21, 2007; Accepted June 21, 2007

Friedreich ataxia, the most common recessive ataxia, is due to deficiency of the mitochondrial protein frataxin, an iron chaperone involved in the assembly of Fe-S clusters (ISC). In yeast, mitochondria play a central role for all Fe-S proteins, independently of their subcellular localization. In mammalian cells, this central role of mitochondria remains controversial as an independent cytosolic ISC assembly machinery has been suggested. In the present work, we show that three extramitochondrial Fe-S proteins (xanthine oxido-reductase, glutamine phosphoribosylpyrophosphate amidotransferase, and Nth1) are affected in frataxin-deleted mouse tissues. Furthermore, we show that frataxin is strictly localized to the mitochondria, excluding the presence of a cytosolic pool of frataxin in normal adult tissues. Together, these results demonstrate that in mammals, frataxin and mitochondria play a cardinal role in the maturation of extramitochondrial Fe-S proteins. Furthermore, we show that the Fe-S scaffold protein IscU progressively decreases in frataxin-deleted tissues, further contributing to the impairment of Fe-S proteins. These results thus provide new cellular pathways that may contribute to molecular mechanisms of the disease.

{dagger} These authors have contributed equally to this work.


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