AUTHOR=Monfort Beata , Want Kristian , Gervason Sylvain , D’Autréaux Benoit 

TITLE=Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 16 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.838335

DOI=10.3389/fnins.2022.838335

ISSN=1662-453X

ABSTRACT=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 65 % to 98 %, which foremost affects the cerebellum, the heart, and the liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery, which has hindered the development of enzymatic assays to screen for drugs that could selectively replace the FXN protein. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and also heme, iron accumulation and deposition in mitochondria and sensitivity to oxidative stress. Based on these phenotypes and the 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 pointing to a unique function of FXN as an enhancer accelerating a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.