Friedreich ataxia (FRDA), the most common autosomal recessive inherited ataxic disorder, is the consequence of deficiency of the
mitochondrial protein frataxin, typically caused by homozygous intronic GAA expansions in the corresponding gene. The yeast
frataxin homologue (yfh1p) is required for cellular respiration. Yfh1p appears to regulate mitochondrial
iron homeostasis and protect from
free radical toxicity. Complete loss of
frataxin in knockout mice leads to early embryonic lethality, indicating an important role for
frataxin during development. Heterozygous littermates with partial
frataxin deficiency are apparently healthy and have no obvious phenotype. Here we evaluate
iron metabolism and sensitivity to dietary and parenteral
iron loading in heterozygote
frataxin knockout mice (Fx(+/-)).
Iron concentrations in the liver, heart, pancreas and spleen, and cellular
iron distribution patterns were compared between wild type and Fx(+/-) mice. Response to parenteral
iron challenge was not different between Fx(+/-) mice and wild type littermates, while sporadic
iron deposits were observed in the hearts of
dietary iron-loaded Fx(+/-) mice. Finally, we evaluated the effect of partial
frataxin deficiency on susceptibility to cardiac damage in the mouse model of hereditary
hemochromatosis (HH), the Hfe knockout mice. HH, an
iron overload disease, is one of the most frequent
genetic diseases in populations of European origin. By breeding Hfe(-/-) with Fx(+/-) mice, we obtained compound mutant mice lacking both Hfe and one
frataxin allele. Sparse
iron deposits in areas of mild to moderate cardiac
fibrosis were found in the majority of these mice. However, they did not develop any neurological symptoms. Our studies indicate an association between
frataxin deficiency, iron deposits and cardiac
fibrosis, but no obvious association between
iron accumulation and neurodegeneration similar to FRDA could be detected in our model. In addition, these results suggest that
frataxin mutations may have a modifier role in HH, that predisposes to
cardiomyopathy.