Monfort Beata, Want Kristian, Gervason Sylvain, D'Autréaux Benoit
Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France.
Front Neurosci. 2022 Mar 2;16:838335. doi: 10.3389/fnins.2022.838335. eCollection 2022.
Friedreich's ataxia (FRDA) is the most prevalent autosomic recessive ataxia and is associated with a severe cardiac hypertrophy and less frequently diabetes. It is caused by mutations in the gene encoding frataxin (FXN), a small mitochondrial protein. The primary consequence is a defective expression of FXN, with basal protein levels decreased by 70-98%, which foremost affects the cerebellum, dorsal root ganglia, heart and liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, iron accumulation and deposition in mitochondria, and sensitivity to oxidative stress. Based on these phenotypes and the proposed ability of FXN to bind iron, a role as an iron storage protein providing iron for Fe-S cluster and heme biosynthesis was initially proposed. However, this model was challenged by several other studies and it is now widely accepted that FXN functions primarily in Fe-S cluster biosynthesis, with iron accumulation, heme deficiency and oxidative stress sensitivity appearing later on as secondary defects. Nonetheless, the biochemical function of FXN in Fe-S cluster biosynthesis is still debated. Several roles have been proposed for FXN: iron chaperone, gate-keeper of detrimental Fe-S cluster biosynthesis, sulfide production stimulator and sulfur transfer accelerator. A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.
弗里德赖希共济失调（FRDA）是最常见的常染色体隐性共济失调，与严重的心脏肥大有关，较少与糖尿病相关。它由编码铁调素（FXN）的基因突变引起，铁调素是一种小的线粒体蛋白。主要后果是FXN表达缺陷，基础蛋白水平降低70 - 98%，这首先影响小脑、背根神经节、心脏和肝脏。FXN是一种参与铁代谢的线粒体蛋白，但其确切功能自发现以来一直难以捉摸且备受争议。在细胞水平上，FRDA的特征是铁硫（Fe - S）簇和血红素生物合成普遍不足、铁在线粒体中积累和沉积以及对氧化应激敏感。基于这些表型以及FXN结合铁的假定能力，最初提出FXN作为铁储存蛋白为Fe - S簇和血红素生物合成提供铁的作用。然而，该模型受到其他几项研究的挑战，现在人们普遍认为FXN主要在Fe - S簇生物合成中起作用，铁积累、血红素缺乏和氧化应激敏感性随后作为次要缺陷出现。尽管如此，FXN在Fe - S簇生物合成中的生化功能仍存在争议。FXN已被提出具有多种作用：铁伴侣、有害Fe - S簇生物合成的守门人、硫化物产生刺激剂和硫转移促进剂。现在出现的一种情况表明，FXN具有独特的功能，即作为Fe - S簇生物合成复合物两个组分之间硫转移关键步骤的促进剂。这些发现应促进FRDA治疗新策略的开发。我们将在此回顾关于铁调素生化功能的最新发现以及对FRDA潜在治疗的意义。
