Friedreich's ataxia is the most important recessive
ataxia in the Caucasian population. Loss of
frataxin expression affects the production of
iron-
sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of
iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive
iron. However, the mechanism underlying this inappropriate mitochondrial
iron accumulation is still unknown. Control and
frataxin-deficient flies were fed with an
iron diet in order to mimic an
iron overload and used to assess various cellular as well as mitochondrial functions. We showed that
frataxin-deficient flies were hypersensitive toward
dietary iron and developed an
iron-dependent decay of mitochondrial functions. In the fly model exhibiting only partial
frataxin loss, we demonstrated that the inability to activate
ferritin translation and the enhancement of mitochondrial
iron uptake via mitoferrin upregulation were likely the key molecular events behind the
iron-induced phenotype. Both defects were observed during the normal process of aging, confirming their importance in the progression of the pathology. In an effort to further assess the importance of these mechanisms, we carried out genetic interaction studies. We showed that mitoferrin downregulation improved many of the
frataxin-deficient conditions, including nervous system degeneration, whereas mitoferrin overexpression exacerbated most of them. Taken together, this study demonstrates the crucial role of mitoferrin dysfunction in the etiology of
Friedreich's ataxia and provides evidence that impairment of mitochondrial
iron transport could be an effective treatment of the disease.