Becker Erika M, Greer Judith M, Ponka Prem, Richardson Des R
Heart Research Institute, Iron Metabolism and Chelation Group, Camperdown, Sydney, New South Wales, Australia.
Blood. 2002 May 15;99(10):3813-22. doi: 10.1182/blood.v99.10.3813.
Friedreich ataxia (FA) is caused by decreased frataxin expression that results in mitochondrial iron (Fe) overload. However, the role of frataxin in mammalian Fe metabolism remains unclear. In this investigation we examined the function of frataxin in Fe metabolism by implementing a well-characterized model of erythroid differentiation, namely, Friend cells induced using dimethyl sulfoxide (DMSO). We have characterized the changes in frataxin expression compared to molecules that play key roles in Fe metabolism (the transferrin receptor [TfR] and the Fe transporter Nramp2) and hemoglobinization (beta-globin). DMSO induction of hemoglobinization results in a marked decrease in frataxin gene (Frda) expression and protein levels. To a lesser extent, Nramp2 messenger RNA (mRNA) levels were also decreased on erythroid differentiation, whereas TfR and beta-globin mRNA levels increased. Intracellular Fe depletion using desferrioxamine or pyridoxal isonicotinoyl hydrazone, which chelate cytoplasmic or cytoplasmic and mitochondrial Fe pools, respectively, have no effect on frataxin expression. Furthermore, cytoplasmic or mitochondrial Fe loading of induced Friend cells with ferric ammonium citrate, or the heme synthesis inhibitor, succinylacetone, respectively, also had no effect on frataxin expression. Although frataxin has been suggested by others to be a mitochondrial ferritin, the lack of effect of intracellular Fe levels on frataxin expression is not consistent with an Fe storage role. Significantly, protoporphyrin IX down-regulates frataxin protein levels, suggesting a regulatory role of frataxin in Fe or heme metabolism. Because decreased frataxin expression leads to mitochondrial Fe loading in FA, our data suggest that reduced frataxin expression during erythroid differentiation results in mitochondrial Fe sequestration for heme biosynthesis.
弗里德赖希共济失调（FA）是由铁调素表达减少导致线粒体铁（Fe）过载引起的。然而，铁调素在哺乳动物铁代谢中的作用仍不清楚。在本研究中，我们通过采用一种特征明确的红细胞分化模型，即使用二甲基亚砜（DMSO）诱导的弗氏细胞，来研究铁调素在铁代谢中的功能。我们已经描述了与在铁代谢中起关键作用的分子（转铁蛋白受体[TfR]和铁转运蛋白Nramp2）以及血红蛋白化（β-珠蛋白）相比，铁调素表达的变化。DMSO诱导的血红蛋白化导致铁调素基因（Frda）表达和蛋白质水平显著降低。在较小程度上，Nramp2信使核糖核酸（mRNA）水平在红细胞分化时也降低，而TfR和β-珠蛋白mRNA水平升高。使用去铁胺或吡啶醛异烟酰腙分别螯合细胞质或细胞质和线粒体铁池来进行细胞内铁耗竭，对铁调素表达没有影响。此外，分别用柠檬酸铁铵或血红素合成抑制剂琥珀酰丙酮对诱导的弗氏细胞进行细胞质或线粒体铁加载，对铁调素表达也没有影响。尽管其他人认为铁调素是一种线粒体铁蛋白，但细胞内铁水平对铁调素表达缺乏影响与铁储存作用不一致。值得注意的是，原卟啉IX下调铁调素蛋白水平，提示铁调素在铁或血红素代谢中具有调节作用。由于铁调素表达降低会导致FA中的线粒体铁加载，我们的数据表明，红细胞分化过程中铁调素表达降低会导致线粒体铁被隔离用于血红素生物合成。
