马萨诸塞州总医院Vamsi K. Mootha小组的最新研究探明了线粒体铁氧化还蛋白FDX2突变抑制frataxin缺乏。该研究于2025年12月10日发表于国际一流学术期刊《自然》杂志上。

在这里，研究人员在秀丽隐杆线虫中进行了一项无偏倚的、基因组尺度的正向遗传筛选，利用允许和非允许的氧张力来发现绕过对fraataxin需求的抑制突变。所有突变都主要发生在铁氧还蛋白FDX2/fdx-2或半胱氨酸脱硫酶NFS1/nfs-1基因中，导致FDX2 - NFS1结合界面上的氨基酸取代。他们的遗传和生化分析表明，在缺乏fraataxin的情况下，抑制突变提高了铁硫浓度。

研究人员还证明，过量的FDX2在体外抑制frataxin刺激的NFS1活性，并阻断哺乳动物细胞培养中铁硫细胞的合成。这些发现与结构和生化证据一致，即frataxin和FDX2在NFS1上竞争占据同一位点。研究团队发现，通过丢失一个基因拷贝来降低野生型FDX2的水平，可以改善fraataxin突变体秀丽隐杆线虫的生长或在常氧条件下弗里德里希共济失调的同位模型的共济失调表型。这些遗传和生化研究表明，通过部分敲低FDX2来恢复frataxin和FDX2的化学计量平衡可能是治疗弗里德赖希共济失调的潜在方法。

据悉，Frataxin是一种古老的线粒体铁硫细胞生物合成机制的关键组成部分，作为半胱氨酸脱硫酶NFS1的变构激活剂。共济失调症是最常见的遗传性共济失调症。酵母菌、秀丽隐杆线虫和人类细胞在“允许的”低氧环境中生长时，可以忍受Fraataxin的损失。

附：英文原文

Title: Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency

Author: Meisel, Joshua D., Joshi, Pallavi R., Spelbring, Amy N., Wang, Hong, Wellner, Sandra M., Wiesenthal, Presli P., Miranda, Maria, McCoy, Jason G., Barondeau, David P., Ruvkun, Gary, Mootha, Vamsi K.

Issue&Volume: 2025-12-10

Abstract: Frataxin is a key component of an ancient, mitochondrial iron–sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1,2,3,4,5). Loss of frataxin levels underlies Friedreich’s ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in ‘permissive’ low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2–NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron–sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron–sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich’s ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich’s ataxia.

DOI: 10.1038/s41586-025-09821-2

Source: https://www.nature.com/articles/s41586-025-09821-2