Abstract
Friedreich's ataxia (FRDA) is caused by low expression of frataxin, a small mitochondrial protein. Studies with both yeast and mammals have suggested that decreased frataxin levels lead to elevated intramitochondrial concentrations of labile (chelatable) iron, and consequently to oxidative mitochondrial damage. Here, we used the mitochondrion-selective fluorescent iron indicator/chelator rhodamine B-[(1,10-phenanthrolin-5-yl)aminocarbonyl]benzylester (RPA) to determine the mitochondrial chelatable iron of FRDA patient lymphoblast and fibroblast cell lines, in comparison with age- and sex-matched control cells. No alteration in the concentration of mitochondrial chelatable iron could be observed in patient cells, despite strongly decreased frataxin levels. Uptake studies with (55)Fe-transferrin and iron loading with ferric ammonium citrate revealed no significant differences in transferrin receptor density and iron responsive protein/iron regulatory element binding activity between patients and controls. However, sensitivity to H(2)O(2) was significantly increased in patient cells, and H(2)O(2) toxicity could be completely inhibited by the ubiquitously distributing iron chelator 2,2'-dipyridyl, but not by the mitochondrion-selective chelator RPA. Our data strongly suggest that frataxin deficiency does not affect the mitochondrial labile iron pool or other parameters of cellular iron metabolism and suggest a decreased antioxidative defense against extramitochondrial iron-derived radicals in patient cells. These results challenge current concepts favoring the use of mitochondrion-specific iron chelators and antioxidants to treat FRDA.
Highlights
Friedreich’s ataxia (FRDA) is caused by low expression of frataxin, a small mitochondrial protein
In accordance with the often proposed antioxidant function of frataxin, antioxidant enzyme levels have been found to be significantly different in blood from FRDA patients compared with controls [15], frataxin has been reported to play a critical role in repair of mitochondrial Fe/S clusters in mitochondrial aconitase [12], and it has been shown that superoxide dismutase (SOD) genes are not induced by oxidative stress in FRDA fibroblasts, in contrast to control cells [10, 16, 17]
Mitochondrial Chelatable Iron in Cultured Human FRDA and Control Fibroblasts and Lymphoblasts—The nature of the iron that has been reported to accumulate within the mitochondria of patients with Friedreich’s ataxia is yet unknown
Summary
Friedreich’s ataxia (FRDA) is caused by low expression of frataxin, a small mitochondrial protein Studies with both yeast and mammals have suggested that decreased frataxin levels lead to elevated intramitochondrial concentrations of labile (chelatable) iron, and to oxidative mitochondrial damage. Our data strongly suggest that frataxin deficiency does not affect the mitochondrial labile iron pool or other parameters of cellular iron metabolism and suggest a decreased antioxidative defense against extramitochondrial iron-derived radicals in patient cells. These results challenge current concepts favoring the use of mitochondrion-specific iron chelators and antioxidants to treat FRDA. We studied the influence of decreased frataxin levels on various other parameters of iron metabolism as well as the contribution of mitochondrial chelatable iron to cell death under H2O2-induced oxidative stress in FRDA patient cells
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