Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused 
by a deficiency of frataxin, a conserved mitochondrial protein of unknown 
function. Mitochondrial iron accumulation, loss of iron-sulfur 
cluster-containing enzymes and increased oxidative damage occur in yeast and 
mouse frataxin-depleted mutants as well as tissues and cell lines from FRDA 
patients, suggesting that frataxin may be involved in export of iron from the 
mitochondria, synthesis of iron-sulfur clusters and/or protection from oxidative 
damage. We have previously shown that yeast frataxin has structural and 
functional features of an iron storage protein. In this study we have 
investigated the function of human frataxin in Escherichia coli and 
Saccharomyces cerevisiae. When expressed in E.coli, the mature form of human 
frataxin assembles into a stable homopolymer that can bind approximately 10 
atoms of iron per molecule of frataxin. The iron-loaded homopolymer can be 
detected on non-denaturing gels by either protein or iron staining demonstrating 
a stable association between frataxin and iron. As analyzed by gel filtration 
and electron microscopy, the homopolymer consists of globular particles of 
approximately 1 MDa and ordered rod-shaped polymers of these particles that 
accumulate small electron-dense cores. When the human frataxin precursor is 
expressed in S.cerevisiae, the mitochondrially generated mature form is 
separated by gel filtration into monomer and a high molecular weight pool of 
>600 kDa. A high molecular weight pool of frataxin is also present in mouse 
heart indicating that frataxin can assemble under native conditions. In 
radiolabeled yeast cells, human frataxin is recovered by immunoprecipitation 
with approximately five atoms of (55)Fe bound per molecule. These findings 
suggest that FRDA results from decreased mitochondrial iron storage due to 
frataxin deficiency which may impair iron metabolism, promote oxidative damage 
and lead to progressive iron accumulation.