Ferredoxins comprise a large family of iron-sulfur (Fe-S) proteins that shuttle electrons in diverse biological processes. Human mitochondria contain two isoforms of [2Fe-2S] ferredoxins, FDX1 (aka adrenodoxin) and FDX2, with known functions in cytochrome P450-dependent steroid transformations and Fe-S protein biogenesis. Here, we show that only FDX2, but not FDX1, is involved in Fe-S protein maturation. Vice versa, FDX1 is specific not only for steroidogenesis, but also for heme a and lipoyl cofactor biosyntheses. In the latter pathway, FDX1 provides electrons to kickstart the radical chain reaction catalyzed by lipoyl synthase. We also identified lipoylation as a target of the toxic antitumor copper ionophore elesclomol. Finally, the striking target specificity of each ferredoxin was assigned to small conserved sequence motifs. Swapping these motifs changed the target specificity of these electron donors. Together, our findings identify new biochemical tasks of mitochondrial ferredoxins and provide structural insights into their functional specificity.

Centre for Synthetic Microbiology Synmikro Marburg Germany

Department of Biochemistry and Molecular Biology The Pennsylvania State University University Park PA USA

Department of Biochemistry Faculty of Chemistry Philipps University of Marburg Marburg Germany

Department of Chemistry The Pennsylvania State University University Park PA USA

Freelance Medical Communications Consultant Brno Czech Republic

Institute for Cytobiology Philipps University of Marburg Marburg Germany

The Howard Hughes Medical Institute The Pennsylvania State University University Park PA USA

Univ of Grenoble Alpes CNRS UMR 5525 VetAgro Sup Grenoble INP TIMC Grenoble France

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Nat Chem Biol. 2023 Feb;19(2):129-130. doi: 10.1038/s41589-022-01176-3. PubMed

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