title: Frataxin inactivation leads to steroid deficiency in flies and human ovarian cells.
abstract: Friedreich ataxia (FA), the most common inherited autosomal-recessive ataxia in Caucasians, is characterized by progressive degeneration of the central and peripheral nervous system, hypertrophic cardiomyopathy and increased incidence of diabetes. FA is caused by a GAA repeat expansion in the first intron of the gene encoding frataxin, an evolutionarily conserved mitochondrial protein, which results in decreased gene expression. Ubiquitous inactivation of the fly frataxin ortholog dfh blocks the transition from larval to pupal stages. In this study, we show that this phenotype is due to ecdysteroid deficiency and that feeding larvae with the 20-hydroxyecdysone steroid hormone rescues this developmental blockage. In mammals, adrenodoxin, the ferredoxin FDX1, is an Fe-S-containing protein essential for the synthesis of various steroid hormones. We show here that the two fly ferredoxins, Fdxh and Fdxh2 (encoded by CG1319), are also involved in steroidogenesis. This provides a potent mechanism by which frataxin, known to be involved in Fe-S cluster biosynthesis, could affect steroidogenesis through reduced ferredoxin activity. Finally, we show that frataxin inactivation decreases progesterone synthesis in human KGN ovarian granulosa cells. Thus, the involvement of frataxin in steroid synthesis appears to be a conserved function of the protein from flies to human and our data suggest that steroidogenesis could be affected in FA patients.
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Paris, France and.
authors: Amandine
authors: A
authors: Palandri
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Paris, France and INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France.
authors: David
authors: D
authors: L'hôte
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Paris, France and INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France.
authors: Joëlle
authors: J
authors: Cohen-Tannoudji
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Paris, France and.
authors: Hervé
authors: H
authors: Tricoire
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Paris, France and veronique.monnier@univ-paris-diderot.fr.
authors: Véronique
authors: V
authors: Monnier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D004175:Diptera; D026461:Ecdysteroids / Q000172:deficiency; D004441:Ecdysterone / Q000008:administration & dosage; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D056726:Genetic Association Studies; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D010053:Ovary / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D011374:Progesterone / Q000096:biosynthesis; D034622:RNA Interference; D013256:Steroids / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D026461:Ecdysteroids; D004441:Ecdysterone; D033862:Iron-Binding Proteins; D011374:Progesterone; D013256:Steroids; D000096923:Frataxin