RRC ID 67524
Author Palandri A, L'hôte D, Cohen-Tannoudji J, Tricoire H, Monnier V.
Title Frataxin inactivation leads to steroid deficiency in flies and human ovarian cells.
Journal Hum Mol Genet
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.
Volume 24(9)
Pages 2615-26
Published 2015-5-1
DOI 10.1093/hmg/ddv024
PII ddv024
PMID 25628335
MeSH Animals Animals, Genetically Modified Cell Line Diptera Ecdysteroids / deficiency Ecdysterone / administration & dosage Female Friedreich Ataxia / genetics Friedreich Ataxia / metabolism Gene Silencing* Genetic Association Studies* Granulosa Cells / drug effects Granulosa Cells / metabolism Humans Iron-Binding Proteins / genetics* Iron-Binding Proteins / metabolism Larva / drug effects Larva / genetics Larva / growth & development Larva / metabolism Ovary / cytology* Ovary / metabolism* Phenotype Progesterone / biosynthesis RNA Interference Steroids / metabolism*
IF 5.101
Human and Animal Cells KGN(RCB1154)