Cross-regulation of [2Fe–2S] cluster synthesis by ferredoxin-2 and frataxin

Want, K., Gorny, H., Turki, E. et al. Cross-regulation of [2Fe–2S] cluster synthesis by ferredoxin-2 and frataxin. Nature (2025). doi: 10.1038/s41586-025-09822-1 

 Using an in-vitro-reconstituted human system, we show that any deviation from a close-to-equal amount of FXN and FDX2 downregulates Fe–S cluster synthesis. Structure–function investigation reveals that this is due to competition between FXN and FDX2 and their similar affinities for the same binding site on the NFS1–ISCU2 complex, with higher levels of FXN impairing the persulfide reductase activity of FDX2 and higher levels of FDX2 slowing the FXN-accelerated transfer of persulfide to ISCU2. We also find that FDX2 directly hinders persulfide generation and transfer to ISCU2 by interacting with the persulfide-carrying mobile loop of NFS1. We further show that knocking down the expression of FDX2 increases fly lifespan in a Drosophila model of Friedreich’s ataxia. Together, this work highlights a direct regulation of Fe–S cluster biosynthesis through antagonistic binding of FXN and FDX2, and suggests that decreasing FDX2 in the context of FXN deficiency in Friedreich’s ataxia might constitute a novel therapeutic axis.