Iron Regulatory Protein-1 Protects against Mitoferrin-1-deficient Porphyria
Iron Regulatory Protein-1 Protects against Mitoferrin-1-deficient Porphyria
复制标题
DOI：
10.1074/jbc.m114.547778
复制
发表时间：
2014-03-14
影响因子：
4.8
通讯作者：
Paw, Barry H.
中科院分区：
文献类型：
--
作者：
Chung, Jacky;Anderson, Sheila A.;Paw, Barry H.
背景：血红素和[Fe-S]簇组装是一个严格调控的过程，需要线粒体铁。结果：线粒体铁的缺失激活了IRP1的[Fe-S]依赖性rna结合活性，从而抑制了原卟啉的生物合成。结论：IRP1形成了一个关键的反馈机制，在限制线粒体铁条件下阻止原卟啉积累。意义：本研究为血红素的生物发生与[Fe-S]簇的合成提供了证据。线粒体铁对于哺乳动物细胞中血红素和铁硫（[Fe-S]）簇的生物合成至关重要。在发育中的红细胞中，铁通过MFRN1 （mitoferrin-1, SLC25A37）进入线粒体。尽管在斑马鱼和小鼠中MFRN1的缺失会导致深度贫血，但突变动物没有表现出明显的卟啉症迹象，这表明线粒体铁缺乏不会导致原卟啉的积累。在这里，我们建立了一个基因陷阱模型，以提供体外和体内证据，证明铁调节蛋白-1 （IRP1）抑制原卟啉的积累。Mfrn1 (+ / gt);Irp1（-/-）红细胞显示出原卟啉水平的显著增加。IRP1通过与alas2mrna的5-铁反应元件（IRE）结合，抑制其翻译，从而减弱原卟啉的生物合成。在Mfrn1（gt/gt）细胞中，携带突变体IRE的alas2异位表达可阻止IRP1结合，模拟IRP1缺乏。总之，我们的数据支持一个模型，即Mfrn1（gt/gt）细胞中线粒体[Fe-S]簇生物发生受损导致IRP1 rna结合升高，从而减弱ALAS2 mRNA的翻译和原卟啉的积累。
Background: Heme and [Fe-S] cluster assembly are tightly regulated processes that require mitochondrial iron. Results: Loss of mitochondrial iron activates the [Fe-S]-dependent RNA-binding activity of IRP1 that inhibits protoporphyrin biosynthesis. Conclusion: IRP1 forms a critical feedback mechanism, preventing protoporphyrin accumulation under limiting mitochondrial iron conditions. Significance: This study provides evidence linking heme biogenesis to that of [Fe-S] clusters synthesis.Mitochondrial iron is essential for the biosynthesis of heme and iron-sulfur ([Fe-S]) clusters in mammalian cells. In developing erythrocytes, iron is imported into the mitochondria by MFRN1 (mitoferrin-1, SLC25A37). Although loss of MFRN1 in zebrafish and mice leads to profound anemia, mutant animals showed no overt signs of porphyria, suggesting that mitochondrial iron deficiency does not result in an accumulation of protoporphyrins. Here, we developed a gene trap model to provide in vitro and in vivo evidence that iron regulatory protein-1 (IRP1) inhibits protoporphyrin accumulation. Mfrn1(+/gt);Irp1(-/-) erythroid cells exhibit a significant increase in protoporphyrin levels. IRP1 attenuates protoporphyrin biosynthesis by binding to the 5-iron response element (IRE) of alas2 mRNA, inhibiting its translation. Ectopic expression of alas2 harboring a mutant IRE, preventing IRP1 binding, in Mfrn1(gt/gt) cells mimics Irp1 deficiency. Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1(gt/gt) cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation.