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

"The whole process is enhanced by FXN, which accelerates the transfer of persulfide between NFS1 and ISCU2 (refs. 12,14,15). Any defect in the synthesis of Fe-S clusters leads to severe diseases8,9,10, the most frequent of which is Friedreich's ataxia, a neurodegenerative and cardiac disease caused by defective FXN expression11. Therapeutic strategies for Friedreich's ataxia have focused on increasing the levels of FXN, with gene therapy being the most promising approach20,21,22."

"However, the acute toxicity associated with FXN overexpression presents challenges23,24,25,26. This toxicity has been shown to rely on defective Fe-S cluster biosynthesis in vivo27, suggesting that a feedback loop exists in which FXN negatively affects the system that it stimulates. Indeed, biochemical data show that FXN and FDX2 share the same binding site in the NFS1-ISCU2 complex28,29,30, which suggests that these two proteins could interfere with each other's activity."

Fe-S clusters assemble in mitochondria beginning with [2Fe-2S] synthesis on scaffold protein ISCU2. Iron binding to ISCU2 triggers persulfide acquisition from the NFS1–ISD11–ACP cysteine desulfurase complex, followed by persulfide cleavage by FDX2 to form a [1Fe-1S] precursor and ISCU2 dimerization into [2Fe-2S] clusters. Frataxin (FXN) accelerates persulfide transfer between NFS1 and ISCU2. Defective Fe-S biosynthesis causes diseases such as Friedreich's ataxia. FXN overexpression produces acute toxicity linked to impaired Fe-S cluster assembly. FXN and FDX2 share the same NFS1–ISCU2 binding site and mutually interfere, with FDX2 directly inhibiting persulfide generation and transfer.

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