File:Role of FXN Gene in Friedriech Ataxia.jpg

A model of how cytosolic iron depletion decreases expression of frataxin in FA patients and may thereby exacerbate disease. Frataxin deficiency mainly caused by the triplet GAA repeat expansion in the first intron of frataxin gene leads to decreased frataxin expression and impairment of mitochondrial iron–sulfur cluster [Fe–S] assembly. Mitochondrial iron overload develops as a consequence of deficient [Fe–S] assembly in mitochondria which leads to misregulation of mitochondrial iron homeostasis. Excess mitochondrial iron uptake and sequestration causes cytosolic iron depletion, which can further diminish frataxin expression by decreasing frataxin transcription. Thus, the decrease in frataxin levels caused by the trinucleotide repeat may be worsened as cells accumulate mitochondrial iron and deplete cytosolic iron stores. This negative feedback loop may contribute to progression of disease in long-lived cells, particularly neurons and cardiomyocytes