Palandri Amandine, L'hôte David, Cohen-Tannoudji Joëlle, Tricoire Hervé, Monnier Véronique
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Paris, France and.
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.
Hum Mol Genet. 2015 May 1;24(9):2615-26. doi: 10.1093/hmg/ddv024. Epub 2015 Jan 26.
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.
弗里德赖希共济失调（FA）是白种人中最常见的常染色体隐性遗传性共济失调，其特征为中枢和周围神经系统进行性退化、肥厚性心肌病以及糖尿病发病率增加。FA是由编码酵母辅酶Q蛋白（一种进化上保守的线粒体蛋白）的基因的第一个内含子中的GAA重复序列扩增引起的，这导致基因表达降低。果蝇酵母辅酶Q直系同源物dfh的普遍失活会阻止幼虫向蛹期的转变。在本研究中，我们表明这种表型是由于蜕皮类固醇缺乏所致，并且用20-羟基蜕皮酮类固醇激素喂养幼虫可挽救这种发育阻滞。在哺乳动物中，肾上腺铁氧化还原蛋白，即铁氧化还原蛋白FDX1，是一种含Fe-S的蛋白质，对各种类固醇激素的合成至关重要。我们在此表明，果蝇的两种铁氧化还原蛋白Fdxh和Fdxh2（由CG1319编码）也参与类固醇生成。这提供了一种有力的机制，通过该机制，已知参与Fe-S簇生物合成的酵母辅酶Q可以通过降低铁氧化还原蛋白活性来影响类固醇生成。最后，我们表明酵母辅酶Q失活会降低人KGN卵巢颗粒细胞中的孕酮合成。因此，酵母辅酶Q参与类固醇合成似乎是该蛋白从果蝇到人类的保守功能，我们的数据表明FA患者的类固醇生成可能会受到影响。
