巴黎萨克雷大学Benoit D’Autréaux小组的一项最新研究提出了铁氧化还原蛋白-2与frataxin对[2Fe-2S]簇合成的交叉调控。2025年12月10日，国际知名学术期刊《自然》发表了这一成果。

在这里，研究小组证明了高效的Fe-S电池组装需要FXN和铁氧化还原蛋白-2 （FDX2）比例的微调平衡。Fe-S细胞组装在支架蛋白ISCU2上；硫由NFS1提供为过硫化物，由FDX2裂解为硫化物，FXN通过加速过硫化物向ISCU2的转移来刺激整个过程。利用体外重建的人体系统，研究人员发现任何偏离接近等量的FXN和FDX2都会下调Fe-S色谱仪的合成。结构-功能研究表明，这是由于FXN和FDX2之间的竞争以及它们对NFS1-ISCU2复合物上相同结合位点的相似亲和力，高水平的FXN会损害FDX2的过硫还原酶活性，高水平的FDX2会减慢FXN加速过硫向ISCU2的转移。

课题组研究人员还发现FDX2通过与NFS1携带过硫化物的移动环相互作用，直接阻碍过硫化物的产生和向ISCU2转移。课题组进一步表明，在弗里德里希共济失调的果蝇模型中，敲低FDX2的表达可以延长果蝇的寿命。总之，这项工作强调了通过FXN和FDX2的拮抗结合直接调节Fe-S细胞的生物合成，并表明在弗里德赖希共济失调中FXN缺乏的情况下减少FDX2可能构成一种新的治疗轴。

据了解，铁硫离子（Fe-S）是重要的金属辅助因子，具有多种生物功能。它们的合成受到严格调控，这一过程中的缺陷会导致严重的疾病，如弗里德赖希共济失调，这是由frataxin （FXN）表达缺陷引起的。然而，调控这一过程的潜在机制尚不清楚。

附：英文原文

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

Author: Want, Kristian, Gorny, Hubert, Turki, Ema, Noiray, Magali, Monfort, Beata, Mor-Gautier, Rmi, Tubiana, Thibault, Jullian, Estelle, Monnier, Vronique, DAutraux, Benoit

Issue&Volume: 2025-12-10

Abstract: Iron–sulfur (Fe–S) clusters are essential metallocofactors that perform a multitude of biological functions1,2,3,4,5,6,7. Their synthesis is tightly regulated and defects in this process lead to severe diseases8,9,10, such as Friedreich’s ataxia, which is caused by defective expression of frataxin (FXN)11. However, the underlying mechanisms that regulate this process remain unclear. Here we show that efficient Fe–S cluster assembly requires a fine-tuned balance in the ratio of FXN and ferredoxin-2 (FDX2). Fe–S clusters are assembled on the scaffold protein ISCU2; sulfur is provided as a persulfide by NFS1, and the persulfide is cleaved into sulfide by FDX2 (refs. 12,13). FXN stimulates the whole process by accelerating the transfer of persulfide to ISCU2 (refs. 12,14,15). 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.

DOI: 10.1038/s41586-025-09822-1

Source: https://www.nature.com/articles/s41586-025-09822-1