Frataxin, mitochondrial (FXN)

Frataxin is a nuclear-encoded mitochondrial protein that is essential for cellular iron homeostasis and the biogenesis of iron-sulfur (Fe-S) clusters. It acts as an iron chaperone, delivering ferrous iron to the scaffold protein ISCU to facilitate the assembly of Fe-S clusters, which are vital components of the mitochondrial respiratory chain and various metabolic enzymes like aconitase. A deficiency in frataxin, most commonly caused by a GAA trinucleotide repeat expansion in the FXN gene, leads to Friedreich's ataxia, a debilitating multisystem disorder characterized by progressive neurodegeneration and hypertrophic cardiomyopathy. This deficiency results in mitochondrial iron accumulation, increased production of reactive oxygen species, and severely impaired ATP production. Therapeutic interventions targeting frataxin aim to restore its levels through gene therapy, protein replacement, or small molecules that enhance endogenous expression by reversing epigenetic silencing or activating protective pathways like Nrf2. However, drug development must carefully manage the therapeutic window, as excessive frataxin overexpression has been shown to induce mitochondrial dysfunction and cardiotoxicity in preclinical models.

Other names

FrataxinFXNFRDAX25CyaY-like proteinFriedreich ataxia proteinFARR