Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts
Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts
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铁调节蛋白缺乏会损害小鼠胚胎成纤维细胞的线粒体功能
DOI：
10.1038/s41598-018-23175-y
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发表时间：
2018-03-23
影响因子：
4.6
通讯作者：
Li, Kuanyu
中科院分区：
文献类型：
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作者：
Li, Huihui;Zhao, Hongting;Li, Kuanyu
铁对哺乳动物细胞的生长和增殖是必不可少的。铁调节蛋白(IRPS)通过与靶mRNAs中的同源铁反应元件结合，从而调节靶基因的表达，从而调节细胞铁稳态的维持。已知Irp1或Irp2零突变通过降低转铁蛋白受体1和增加铁蛋白来降低细胞铁水平。在这里，我们报告了Irp1或Irp2零突变也导致Frataxin和IscU的下调，这是铁-硫簇生物发生机制中的两个核心成分。有趣的是，虽然包括线粒体乌头酸酶和胞浆黄嘌呤氧化酶在内的一些含铁硫簇的酶的活性没有受到突变的影响，但呼吸链复合体的活性显著降低，导致线粒体功能障碍。人ISCU和Frataxin在Irp1或Irp2缺失细胞中的过表达能够修复铁-硫簇生物发生和线粒体质量的缺陷。我们的结果强烈表明，铁调节蛋白调控铁硫簇生物发生的一部分，该生物发生是专为线粒体电子传递链复合体定制的。
Iron is essential for growth and proliferation of mammalian cells. The maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs) through binding to the cognate iron-responsive elements in target mRNAs and thereby regulating the expression of target genes. Irp1 or Irp2-null mutation is known to reduce the cellular iron level by decreasing transferrin receptor 1 and increasing ferritin. Here, we report that Irp1 or Irp2-null mutation also causes downregulation of frataxin and IscU, two of the core components in the iron-sulfur cluster biogenesis machinery. Interestingly, while the activities of some of iron-sulfur cluster-containing enzymes including mitochondrial aconitase and cytosolic xanthine oxidase were not affected by the mutations, the activities of respiratory chain complexes were drastically diminished resulting in mitochondrial dysfunction. Overexpression of human ISCU and frataxin in Irp1 or Irp2-null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality. Our results strongly suggest that iron regulatory proteins regulate the part of iron sulfur cluster biogenesis tailored specifically for mitochondrial electron transport chain complexes.