Frataxin is a protein that in humans is encoded by the FXN gene. It is located in the mitochondrion and Frataxin mRNA is mostly expressed in tissues with a high metabolic rate. The function of frataxin is not clear but it is involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein. Reduced expression of frataxin is the cause of Friedreich's ataxia. Structure X-ray crystallography has shown that human frataxin consists of a β-sheet that supports a pair of parallel α-helices, forming a compact αβ sandwich. Frataxin homologues in other species are similar, sharing the same core structure. However, the frataxin tail sequences, extending from the end of one helix, diverge in sequence and differ in length. Human frataxin has a longer tail sequence than frataxin found in bacteria or yeast. It is hypothesized that the purpose of the tail is to stabilize the protein. Like most mitochondrial proteins, frataxin is synthesized in cytoplasmic ribosomes as large precursor molecules with mitochondrial targeting sequences. Upon entry into mitochondria, the molecules are broken down by a proteolytic reaction to yield mature frataxin. Function Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein. Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin.). Clinical significance Reduced expression of frataxin is the cause of Friedreich's ataxia (FRDA), a neurodegenerative disease. The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in bacteria and Human cells or both. The expansion of intronic trinucleotide