Friedreich's Ataxia, No Changes in Mitochondrial Labile Iron in Human Lymphoblasts and Fibroblasts
Friedreich's Ataxia, No Changes in Mitochondrial Labile Iron in Human Lymphoblasts and Fibroblasts
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弗里德赖希共济失调，人淋巴母细胞和成纤维细胞中线粒体不稳定铁没有变化
DOI：
10.1074/jbc.m408717200
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发表时间：
2005
影响因子：
4.8
通讯作者：
F. Petrat
中科院分区：
文献类型：
--
作者：
B. Sturm;Ute Bistrich;M. Schranzhofer;J. Sarsero;U. Rauen;B. Scheiber;H. de Groot;P. Ioannou;F. Petrat
弗里德赖希共济失调症（FRDA）是由一种线粒体小蛋白frataxin的低表达引起的。对酵母和哺乳动物的研究表明，卵黄蛋白水平降低会导致线粒体内不稳定（可螯合）铁浓度升高，从而导致线粒体氧化损伤。在这里，我们使用线粒体选择性荧光铁指示剂/螯合剂罗丹明B-[（1,10-邻菲罗啉-5-基）氨基羰基]苄基（RPA）来测定FRDA患者淋巴母细胞和成纤维细胞细胞系的线粒体可螯合铁，并与年龄和性别匹配的对照细胞进行比较。患者细胞中线粒体螯合铁浓度未见变化，尽管卵黄蛋白水平明显降低。55fe -转铁蛋白的摄取研究和柠檬酸铁铵的铁负荷研究显示，患者和对照组在转铁蛋白受体密度和铁反应蛋白/铁调节元件结合活性方面没有显著差异。然而，患者细胞对H2O2的敏感性显著增加，并且H2O2毒性可以被普遍分布的铁螯合剂2,2 ' -dipyridyl完全抑制，而线粒体选择性螯合剂RPA则不能。我们的数据有力地表明，fraataxin缺乏并不影响线粒体不稳定铁池或细胞铁代谢的其他参数，并表明患者细胞对线粒体外铁源自由基的抗氧化防御能力下降。这些结果挑战了目前倾向于使用线粒体特异性铁螯合剂和抗氧化剂治疗FRDA的概念。
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 55Fe-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 H2O2 was significantly increased in patient cells, and H2O2 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.
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影响因子：
3.5
作者：
Campuzano, V;Montermini, L;Koenig, M
通讯作者：
Koenig, M
影响因子：
20.3
作者：
A. M. Konijn;H. Glickstein;B. Vaisman;E. G. Meyron-Holtz;I. N. Slotki;Z. Cabantchik
通讯作者：
A. M. Konijn;H. Glickstein;B. Vaisman;E. G. Meyron-Holtz;I. N. Slotki;Z. Cabantchik
影响因子：
3.5
作者：
Campanella, A;Isaya, G;Levi, S
通讯作者：
Levi, S
影响因子：
56.9
作者：
Babcock, M;deSilva, D;Kaplan, J
通讯作者：
Kaplan, J
DOI：
10.1016/s0079-6603(08)60191-9
发表时间：
1996
期刊：
Progress in nucleic acid research and molecular biology.
影响因子：
--
作者：
Mascotti,DP;Goessling,LS;Rup,D;Thach,RE
通讯作者：
Thach,RE