Human Molecular Genetics Advance Access originally published online on October 27, 2004
Human Molecular Genetics 2004 13(23):3007-3015; doi:10.1093/hmg/ddh324
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Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved
Iron–sulfur protein maturation in human cells: evidence for a function of frataxin
1Institut für Zytobiologie und Zytopathologie, Philipps-Universität, Robert-Koch-Str. 6, 35033 Marburg, Germany and 2Institut für Arbeits- und Sozialmedizin, Justus-Liebig-Universität, Aulweg 129/III, 35392 Giessen, Germany
Received August 18, 2004; Revised September 22, 2004; Accepted October 6, 2004
The maturation of iron–sulfur (Fe/S) proteins in eukaryotes has been intensively studied in yeast. Hardly anything is known so far about the process in higher eukaryotes, even though the high conservation of the yeast maturation components in most Eukarya suggests similar mechanisms. Here, we developed a cell culture model in which the RNA interference (RNAi) technology was used to deplete a potential component of Fe/S protein maturation, frataxin, in human HeLa cells. This protein is lowered in humans with the neuromuscular disorder Friedreich's ataxia (FRDA). Upon frataxin depletion by RNAi, the enzyme activities of the mitochondrial Fe/S proteins, aconitase and succinate dehydrogenase, were decreased, while the activities of non-Fe/S proteins remained constant. Moreover, Fe/S cluster association with the cytosolic iron-regulatory protein 1 was diminished. In contrast, no alterations in cellular iron uptake, iron content and heme formation were found, and no mitochondrial iron deposits were observed upon frataxin depletion. Hence, iron accumulation in FRDA mitochondria appears to be a late consequence of frataxin deficiency. These results demonstrate (i) that frataxin is a component of the human Fe/S cluster assembly machinery and (ii) that it plays a role in the maturation of both mitochondrial and cytosolic Fe/S proteins.
* To whom correspondence should be addressed. Tel: +49 64212866449; Fax: +49 64212866414; Email: lill{at}mailer.uni-marburg.de
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