title: Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin.
abstract: The inability to produce normal levels of the mitochondrial protein frataxin causes the hereditary degenerative disorder Friedreich's Ataxia (FRDA), a syndrome characterized by progressive gait instability, cardiomyopathy and high incidence of diabetes. Frataxin is an iron-binding protein involved in the biogenesis of iron-sulfur clusters (ISC), prosthetic groups allowing essential cellular functions such as oxidative phosphorylation, enzyme catalysis and gene regulation. Although several evidence suggest that frataxin acts as an iron-chaperone within the mitochondrial compartment, we have recently demonstrated the existence of a functional extramitochondrial pool of mature frataxin in various human cell types. Here, we show that a similar proteolytic process generates both mature mitochondrial and extramitochondrial frataxin. To address the physiological function of human extramitochondrial frataxin, we searched for ISC-dependent interaction partners. We demonstrate that the extramitochondrial form of frataxin directly interacts with cytosolic aconitase/iron regulatory protein-1 (IRP1), a bifunctional protein alternating between an enzymatic and a RNA-binding function through the 'iron-sulfur switch' mechanism. Importantly, we found that the cytosolic aconitase defect and consequent IRP1 activation occurring in FRDA cells are reversed by the action of extramitochondrial frataxin. These results provide new insight into the control of cytosolic aconitase/IRP1 switch and expand current knowledge about the molecular pathogenesis of FRDA.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.forename: Florence
authors.initials: F
authors.lastname: Malisan
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guccini
authors.forename: Dario
authors.initials: D
authors.lastname: Serio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D005621:Friedreich Ataxia / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000494:pharmacology*; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D035941:Iron Regulatory Protein 1; D033862:Iron-Binding Proteins; D000096923:Frataxin