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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant
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Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant

机译：通过分析小鼠突变体阐明弗里德赖希共济失调中线粒体铁负荷的机制

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摘要

We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich's ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxi-dase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (ⅰ) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ⅱ) decreased ferroportin1 expression, limiting iron export; (ⅲ) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased "free iron" for mitochondrial uptake; and (ⅳ) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfm2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich's ataxia.
机译：我们使用了肌酸肌酸激酶（MCK）条件性frataxin基因敲除小鼠来阐明frataxin缺乏症如何改变铁代谢。这具有重要意义，因为frataxin缺乏症会导致Friedreich共济失调，这是一种以神经和心脏变性为特征的疾病。使用心脏组织，我们证明frataxin缺乏症导致参与3个线粒体利用途径的关键分子的下调：铁硫簇（ISC）合成（铁硫簇支架蛋白1/2和半胱氨酸脱硫酶Nfs1），线粒体铁储存（线粒体铁蛋白）和血红素合成（5-氨基乙酰丙酸酯脱水酶，原卟啉原氧化酶，羟甲基胆烷合酶，尿卟啉原III合酶和铁螯合酶）。线粒体铁利用率的显着降低以及由此导致的血红素和ISC从线粒体中的释放减少可能导致观察到的线粒体铁过多。通过增加（ⅰ）转铁蛋白受体1上调来增加线粒体摄取铁的可利用性，从而增加铁从转铁蛋白中的摄取，从而增加了这种效应。 （ⅱ）ferroportin1表达降低，限制了铁的输出； （ⅲ）血红素分解代谢酶血红素加氧酶1的表达增加以及铁蛋白-H和-L的下调，都可能导致线粒体摄取的“游离铁”增加； （ⅳ）哺乳动物外囊蛋白Sec15l1和线粒体铁导入剂mitoferrin-2（Mfm2）的表达增加，分别促进细胞铁的摄取和线粒体铁的流入。我们的结果使我们能够构建一个模型，解释在不存在frataxin的情况下胞质铁缺乏和线粒体铁负载的情况，这对于理解Friedreich共济失调的发病机理很重要。

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  • 作者

    Michael Li-Hsuan Huang; Erika M. Becker; Megan Whitnall; Yohan Suryo Rahmanto; Prem Ponka; Des R. Richardson;

  • 作者单位

    lron Metabolism and delation Program, Discipline of Pathology and Bosch Institute, Blackburn Building, D06, University of Sydney, NSW, 2006 Australia;

    lron Metabolism and delation Program, Discipline of Pathology and Bosch Institute, Blackburn Building, D06, University of Sydney, NSW, 2006 Australia;

    lron Metabolism and delation Program, Discipline of Pathology and Bosch Institute, Blackburn Building, D06, University of Sydney, NSW, 2006 Australia;

    lron Metabolism and delation Program, Discipline of Pathology and Bosch Institute, Blackburn Building, D06, University of Sydney, NSW, 2006 Australia;

    Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine Road, Montreal, Quebec, H3T 1E2, Canada;

    lron Metabolism and delation Program, Discipline of Pathology and Bosch Institute, Blackburn Building, D06, University of Sydney, NSW, 2006 Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    heme synthesis; iron; transferrin; frataxin;

    机译：血红素合成铁;转铁蛋白苦参素;

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