Human Molecular Genetics Advance Access originally published online on June 27, 2007
Human Molecular Genetics 2007 16(22):2651-2658; doi:10.1093/hmg/ddm163
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Frataxin is essential for extramitochondrial Fe–S cluster proteins in mammalian tissues
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 and 5 Collège de France, Chaire de Génétique Humaine, Illkirch F-67400, France
* To whom correspondence should be addressed. Tel: +33 388653264; Fax: +33 388653246; Email: 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 caused by the deficiency of the mitochondrial protein frataxin (Fxn), 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 Fxn-deleted mouse tissues. Furthermore, we show that Fxn is strictly localized to the mitochondria, excluding the presence of a cytosolic pool of Fxn in normal adult tissues. Together, these results demonstrate that in mammals, Fxn and mitochondria play a cardinal role in the maturation of extramitochondrial Fe–S proteins. The Fe–S scaffold protein IscU progressively decreases in Fxn-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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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