Frataxin expression rescues mitochondrial dysfunctions in FRDA cells

Friedreich's ataxia (FRDA) is the result of mutations in the nuclear-encode d frataxin gene, which is expressed in mitochondria. Several lines of evide nce have suggested that frataxin is involved in mitochondrial iron homeosta sis. We have transfected the frataxin gene into lymphoblasts of FRDA compou nd heterozygotes (FRDA-CH) with deficient frataxin expression to produce FR DA-CH-t cells in which message and protein are rescued to near-physiologica l levels. FRDA-CH cells were more sensitive to oxidative stress by challeng e with free iron, hydrogen peroxide and the combination, consistent with a Fenton chemical mechanism of pathophysiology, and this sensitivity was resc ued to control levels in FRDA-CH-t cells. Iron challenge caused increased m itochondrial iron levels in FRDA-CH cells, and a decreased mitochondrial me mbrane potential (MMP), both of which were rescued in FRDA-CH-t cells. The rescue of the low MMP, and high mitochondrial iron concentration by frataxi n overexpression suggests that these cellular phenotypes are relevant to th e central pathophysiological process in FRDA which is aggravated by exposur e to free iron. However, even at physiological iron concentrations, FRDA-CH cells had decreased MMP as well as lower activities of aconitase and ICDH (two enzymes supporting MMP), and twice the level of filtrable mitochondria l iron (but no increase in total mitochondrial iron), and the observed phen otypes were either fully or partially rescued in FRDA-CH-t cells. Free iron is known to be toxic. The observation that frataxin deficiency (either dir ectly or indirectly) causes an increase in filtrable mitochondrial iron pro vides a new hypothesis for the mechanism of cell death in this disease, and could be a target for therapy.