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FRDA is an autosomal recessive disease and is the most common hereditary ataxia (1/50,000 live births).¹ The disease results in progressive neurodegeneration and hypertrophic cardiomyopathy, and in about 10% of the cases diabetes mellitus and loss of pancreatic ß cells is seen.² Age of onset is generally around puberty, and as the disease progresses there is increasing ataxia of the limbs, until finally most are wheelchair bound by the twenties. Scoliosis, foot deformities, optic atrophy, and deafness may also occur in FRDA.³

FRDA is caused primarily by a GAA expansion in the first intron of the gene frataxin, and this results in a significantly reduced expression of frataxin mRNA.⁴ The length of the repeat has been associated with disease severity and reduced frataxin expression.¹ It is expressed mainly in the dorsal root ganglia, and it is also expressed in the heart, pancreas, liver, muscle, thymus, and adipose tissue.⁵ This correlates fairly well to disease pathology in that tissues which are most affected are non-dividing and are therefore not replaced if damaged.⁶ Frataxin is a small protein of 210 amino acids encoded by five exons that span a 40 kilobase region of chromosome 9q13-q21.^1,4 It localizes at or near the inner mitochondrial membrane by means of an N-terminal mitochondrial target sequence.⁷ Notably, tissues with high levels of frataxin expression are enriched for mitochondria and are especially dependent upon efficient oxidative phosphorylation.⁸ In the hearts of patients with FRDA, there are increased iron levels, and there is also a deficiency of iron-sulfur (Fe-S) protein activity.⁹ Fe-S proteins are especially sensitive to free radical damage¹⁰, so the lack of Fe-S proteins is most likely due to oxidative stress caused by the abnormal iron levels. Cells deficient in frataxin have also been shown to have increased sensitivity to oxidants, further supporting the idea that damage by oxidative stress is a major disease factor.¹¹ Additionally, the disease characteristics are similar to that of a vitamin E deficiency ataxia, and vitamin E has been shown to be a major anti-oxidant.⁶

Homologous proteins have been identified in the mouse, C. elegans, and S. cerevisiae, with 73%, 49%, and 31% amino acid sequence identity, respectively.⁵ YFH1 is an intronless gene that encodes a 174 amino acid protein with homology to frataxin, especially at the C-terminus, and it has also been shown to localize to the mitochondria.¹² Yeast deletion strains, or null yfh1, show high levels of iron accumulation in the mitochondria and are unable to carry out oxidative phosphorylation. Mutants also lose mitochondrial DNA producing phenotypic petites, presumably as a result of oxidative stress resulting from toxic iron levels.^8,12 Additionally, yeast mutants are also deficient in Fe-S activity.⁹ These results have been confirmed by the identification of mutants of Ssc2p, a mitochondrial Hsp70 homologue that is necessary for YFH1 maturation in the mitochondria.¹³ This suggests that frataxin may be involved in iron transport either by regulating release of mitochondrial iron to the cytoplasm or by inhibiting iron transport into the mitochondria.

Possible targets of YFH1 could be two mitochondrial iron transporters (MFT1 and MFT2) recently discovered in yeast. The transporters appear to be redundant in function as deletion of either gene does not affect cell viability, but double deletion strains exhibit a growth defect on low iron media.¹⁴ Overexpressors of either one or both genes results in iron accumulation in the mitochondria, but this does not result in a defect of oxidative phosphorylation or loss of mitochondrial DNA.¹⁴ As seen in iron damage to organs, it could be very likely that a threshold level is needed before toxicity is attained.¹⁵ The phenotypes of the deletion strains and overexpressing strains leads one to speculate that the transporters may be responsible for both iron efflux and influx into the mitochondria. Transport of iron could be dependent upon cellular iron levels.

One hypothesis is that the mitochondrial iron import system is permanently activated by the lack of frataxin, which may act as a downregulator of mitochondria iron uptake.⁹ A proposed model for iron regulation in the mitochondria is that frataxin acts as a negative regulator of MFT1 and/or MFT2. If MFT1/2 are active in iron transport into the mitochondria at normal or high iron levels, a deletion in frataxin would then result in accumulation of iron to toxic levels. Since little is known about mitochondrial iron transport, it is also possible that frataxin may interact with other unidentified proteins. This possibility needs to be investigated.

Currently, there is no cure or treatment for those afflicted with FRDA, so any clarification of the role frataxin plays will help the search for a cure. Iron chelation therapy has been suggested, but without understanding the actual functional significance of the defect, this could cause complications.¹⁶ Once a target of frataxin is identified, drugs that mimic its function could be developed and provide a treatment.

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