Friedreich ataxia (FA) is an inherited recessive disorder characterized by progressive neurological disability and
heart abnormalities. The
Friedreich ataxia gene (FRDA) encodes a small
mitochondrial protein,
frataxin, which is produced in insufficient amounts in the disease as a consequence of a GAA triplet repeat expansion in the first intron of the gene.
Frataxin deficiency leads to excessive
free radical production, dysfunction of Fe-S center containing
enzymes (in particular respiratory complexes I, II and III, and
aconitase), and progressive
iron accumulation in mitochondria.
Frataxin may be a mitochondrial
iron-binding protein that prevents this
metal from participating in Fenton chemistry to generate toxic
hydroxyl radicals. We investigated whether
frataxin deficiency may in addition interfere with signaling pathways. First, we showed that exposure of FA fibroblasts to
iron fails to produce the normally observed increase in expression of the stress defense
protein manganese superoxide dismutase. This impaired induction involves a
nuclear factor-kappaB-independent pathway that does not require
free radical signaling intermediates. We also examined the role of
frataxin in neuronal differentiation by using stably transfected clones of P19 embryonic
carcinoma cells with antisense or sense
frataxin constructs. We found that during
retinoic acid-induced neurogenesis
frataxin deficiency enhances apoptosis and reduces the number of terminally differentiated neuronal-like cells. The addition of the
antioxidant N-acetyl-
cysteine only rescues cells non-committed to the neuronal lineage, indicating that
frataxin deficiency impairs differentiation mechanisms and survival responses through different mechanisms. Both studies suggest that some abnormalities in
frataxin-deficient cells are related to
free radical independent signaling pathways.