title: Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis.
abstract: Mammalian adrenodoxin (ferredoxin 1; Fdx1) is essential for the synthesis of various steroid hormones in adrenal glands. As a member of the [2Fe-2S] cluster-containing ferredoxin family, Fdx1 reduces mitochondrial cytochrome P450 enzymes, which then catalyze; e.g., the conversion of cholesterol to pregnenolone, aldosterone, and cortisol. The high protein sequence similarity between Fdx1 and its yeast adrenodoxin homologue (Yah1) suggested that Fdx1, like Yah1, may be involved in the biosynthesis of heme A and Fe/S clusters, two versatile and essential protein cofactors. Our study, employing RNAi technology to deplete human Fdx1, did not confirm this expectation. Instead, we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis. Unlike Fdx1, Fdx2 was unable to efficiently reduce mitochondrial cytochromes P450 and convert steroids, indicating that the two ferredoxin isoforms are highly specific for their substrates in distinct biochemical pathways. Moreover, Fdx2 deficiency had a severe impact, via impaired Fe/S protein biogenesis, on cellular iron homeostasis, leading to increased cellular iron uptake and iron accumulation in mitochondria. We conclude that mammals depend on two distinct mitochondrial ferredoxins for the specific production of either steroid hormones or heme A and Fe/S proteins.
authors.affiliation: Institut für Zytobiologie, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35033 Marburg, Germany.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Sheftel
authors.forename: Oliver
authors.initials: O
authors.lastname: Stehling
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Pierik
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mühlenhoff
authors.forename: Holger
authors.initials: H
authors.lastname: Webert
authors.forename: Anna
authors.initials: A
authors.lastname: Hobler
authors.forename: Frank
authors.initials: F
authors.lastname: Hannemann
authors.forename: Rita
authors.initials: R
authors.lastname: Bernhardt
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
mesh_terms: D000325:Adrenodoxin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005288:Ferredoxins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000737:chemistry; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D005288:Ferredoxins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; D013256:Steroids; C120375:YAH1 protein, S cerevisiae; D000325:Adrenodoxin; D006418:Heme; D007501:Iron