title: Iron-sulfur protein maturation in human cells: evidence for a function of frataxin.
abstract: 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.
authors.affiliation: Institut für Zytobiologie und Zytopathologie, Philipps-Universität, Marburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stehling
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
authors.forename: Bernd
authors.initials: B
authors.lastname: Brückel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mühlenhoff
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D033862:Iron-Binding Proteins / Q000502:physiology*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D013385:Succinate Dehydrogenase; D000096923:Frataxin