Friedreich's ataxia, no changes in mitochondrial labile iron in human lymphoblasts and fibroblasts: a decrease in antioxidative capacity?
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.
Sturm
Brigitte
B
Department of Medical Chemistry, Medical University of Vienna, Waehringerstrasse 10, 1090 Vienna, Austria.
Bistrich
Ute
U
Schranzhofer
Matthias
M
Sarsero
Joseph P
JP
Rauen
Ursula
U
Scheiber-Mojdehkar
Barbara
B
de Groot
Herbert
H
Ioannou
Panos
P
Petrat
Frank
F
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology*; D005456:Fluorescent Dyes; D005621:Friedreich Ataxia / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007501:Iron / Q000032:analysis* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000737:chemistry / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000737:chemistry*; D011990:Receptors, Transferrin / Q000032:analysis
D005456:Fluorescent Dyes; D007502:Iron Chelating Agents; D035925:Iron-Regulatory Proteins; D011990:Receptors, Transferrin; D006861:Hydrogen Peroxide; D007501:Iron