The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.

Mutations in the nuclear gene encoding the mitochondrial protein frataxin are responsible for the neurological disorder Friedreich ataxia (FA). Yeast strains with a deletion in the frataxin homologue YFH1 accumulate excess iron in mitochondria and demonstrate mitochondrial damage. We show that in the absence of YFH1, mitochondrial damage is proportional to the concentration and duration of exposure to extracellular iron, establishing mitochondrial iron accumulation as causal to mitochondrial damage. Reintroduction of YFH1 results in the rapid export of accumulated mitochondrial iron into the cytosol as free, non-heme bound iron, demonstrating that mitochondrial iron in the yeast FA model can be made bioavailable. These results demonstrate a mitochondrial iron cycle in which Yfh1p regulates mitochondrial iron efflux.Friedreich ataxia (FA) 1 is a neurodegenerative disease transmitted as an autosomal recessive trait with a prevalence of 1 in 50,000 individuals (1). The FA gene was identified by positional cloning and found to encode a 210-amino acid mitochondrial protein designated frataxin (2). Most cases of FA are because of the expansion of a polymorphic GAA trinucleotide repeat located in the first intron of the frataxin gene, resulting in reduced frataxin mRNA levels (3, 4). The defect responsible for FA also affects non-neuronal organs, and patients usually succumb to a cardiomyopathy in the fourth decade. Gait ataxia is the most common presenting symptom, and most patients eventually manifest dysarthria, areflexia, pyramidal weakness of the legs, extensor planar responses, and distal loss of joint position and vibration sense (1). The frataxin protein is localized to the mitochondria (5), but its function has not been determined. The frataxin protein is highly expressed in neuronal and heart tissue (2), both of which are postmitotic and highly dependent upon mitochondrial respiration (1). Iron deposits have been found in the myocardium of FA patients, and myocardial mitochondrial respiration has been found to be defective (6).Yeast disrupted for YFH1 (yeast frataxin homologue) accumulate iron in mitochondria (7). Mitochondrial DNA (mtDNA) is damaged and mitochondrial respiratory activity is impaired (8,9). Mitochondrial iron accumulation in yeast with YFH1 deletions is associated with subnormal cytosolic iron concentrations (7). Lowered cytosolic iron concentrations induce transcription of FET3, a component of the plasma membrane high affinity iron uptake system (10). The increased rate of iron uptake results in a doubling of cellular iron content relative to wild-type cells, but the excess iron is abnormally localized to mitochondria.Mitochondrial defects in patients with FA and in the yeast model could be a direct result of mitochondrial iron accumulation. Alternatively, a deficiency of frataxin protein could result in mitochondrial damage, and iron overload may be one manifestation of the mitochondrial damage. This phenomenon has been observed in two patients with acquired idiopathic sideroblastic anemi...