Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, P. R. China.
Medical School of Henan Polytechnic University, Jiaozuo, 454000, P. R. China.
Sci Rep. 2018 Mar 23;8(1):5118. doi: 10.1038/s41598-018-23175-y.
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.
铁对于哺乳动物细胞的生长和增殖是必需的。细胞内铁稳态的维持是通过铁调节蛋白（IRP）与靶 mRNA 中的同源铁反应元件结合来调节的，从而调节靶基因的表达。Irp1 或 Irp2 缺失突变已知通过降低转铁蛋白受体 1 和增加铁蛋白来降低细胞内铁水平。在这里，我们报告 Irp1 或 Irp2 缺失突变也会导致铁硫簇生物发生机制的核心组成部分之一的 frataxin 和 IscU 的下调。有趣的是，虽然包括线粒体 aconitase 和细胞质黄嘌呤氧化酶在内的一些含铁硫簇酶的活性不受突变影响，但呼吸链复合物的活性明显降低，导致线粒体功能障碍。在 Irp1 或 Irp2 缺失细胞中转染人 ISCU 和 frataxin 能够挽救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，铁调节蛋白调节专门针对线粒体电子传递链复合物的铁硫簇生物发生的一部分。
