Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1-210; isoform A) expressed in the cytosol of cells rapidly gets moved to the mitochondria, where it is converted to the mature form (81-210). Mature frataxin (81-210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for Friedreich's ataxia. The mitochondrial form of frataxin has long been thought to be present in red blood cells even though they lack mitochondria. This paper shows that frataxin in red blood cells is a novel form of frataxin (called isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times more isoform E in red blood cells from the whole blood of healthy volunteers compared to the mature mitochondrial frataxin present in other blood cells. Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich's ataxia and monitor the efficacy of therapeutic interventions.
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