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首页> 外文期刊>Nature >Mitochondrial Atpifl regulates haem synthesis in developing erythroblasts
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Mitochondrial Atpifl regulates haem synthesis in developing erythroblasts

机译：线粒体Atpifl调节发育中的成红细胞中的血红素合成

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摘要

Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpifl) from a zebrafish mutant with profound anaemia, pinotage (pnt~(tq209)). Here we describe a direct mechanism establishing that Atpifl regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpifl impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpifl-regulated mitochondrial pH and redox potential. Therefore, Atpifl deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpifl as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.
机译：血红素底物的可用性或末端酶在血红素生物合成，铁螯合酶（Fech）中的催化活性存在缺陷，损害血红素合成，从而导致人类先天性贫血。线粒体稳态调节因子和负责血红素合成的酶之间相互依赖的功能在很大程度上是未知的。为了对此进行研究，我们使用了斑马鱼遗传筛选并从具有严重贫血，斑驳症（pnt〜（tq209））的斑马鱼突变体中克隆了线粒体ATPase抑制因子1（atpifl）。在这里，我们描述了一种直接的机制，该机制确定Atpifl调节脊椎动物Fech合成血红素的催化效率。由于Fech活性降低和线粒体pH升高，Atpifl的损失会损害斑马鱼，小鼠和人类造血模型中的血红蛋白合成。为了了解线粒体pH，氧化还原电势，[2Fe-2S]簇与Fech活性之间的关系，我们使用了在pnt中有或没有[2Fe-2S]簇的Fech构建体的遗传互补研究，以及调节线粒体pH和氧化还原电位。 [2Fe-2S]簇的存在使脊椎动物Fech易受Atpifl调节的线粒体pH和氧化还原电位的干扰。因此，Atpifl缺乏症会降低脊椎动物Fech合成血红素的效率，从而导致贫血。线粒体Atpifl作为血红素合成调节剂的鉴定，使我们对调节线粒体血红素稳态和红细胞发育的机制有了更深入的了解。 ATPIF1缺乏症可能导致重要的人类疾病，例如先天性铁粒幼细胞性贫血和线粒体病。

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  • 来源
    《Nature》 |2012年第7425期|p.608-612|共5页
  • 作者

    Dhvanit I. Shah; Naoko Takahashi-Makise; Jeffrey D. Cooney; Liangtao Li; Iman J. Schultz; Eric L. Pierce; Anupama Narla; Alexandra Seguin; Shilpa M. Hattangadi; Amy E. Medlock; Nathaniel B. Langer; Tamara A. Dailey; Slater N. Hurst; Danilo Faccenda; Jessica M. Wiwczar; Spencer K. Heggers; Guillaume Vogin; Wen Chen; Caiyong Chen; Dean R. Campagna; Carlo Brugnara; Yi Zhou; Benjamin L. Ebert; Nika N. Danial; Mark D. Fleming; Diane M. Ward; Michelangelo Campanella; Harry A. Dailey; Jerry Kaplan; Barry H. Paw;

  • 作者单位

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA University of Texas Health Science Center, San Antonio, Texas 78229, USA;

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA InteRNA Technologies, 3584 CH Utrecht, The Netherlands;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Georgia Institute of Technology, Atlanta, Georgia 30332, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Department of Medicine, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312, USA;

    Department of Medicine, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA Yale University, New Haven, Connecticut 06510, USA;

    Biomedical and Health Sciences Institute, Departments of Microbiology, Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Columbia University, New York, New York 10032, USA;

    Biomedical and Health Sciences Institute, Departments of Microbiology, Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Royal Veterinary College, University of London and University College London Consortium for Mitochondrial Research, London NW1 OTU, UK;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA Yale University, New Haven, Connecticut 06510, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Alexis Vautrin Cancer Centre, 54511 Vandoeuvre-Les-Nancy Cedex, France;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Texas A&M Health Science Center, Temple, Texas 76504, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Medicine, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312, USA;

    Royal Veterinary College, University of London and University College London Consortium for Mitochondrial Research, London NW1 OTU, UK;

    Biomedical and Health Sciences Institute, Departments of Microbiology, Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA;

    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312, USA;

    Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA Department of Medicine, Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

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