来自布莱根妇女医院的研究者发现了一种新型基因,其可以在红细胞形成期间调节血红蛋白的合成。该研究可帮助我们增加对生物化学知识的理解以及开发人类贫血和线粒体障碍的新型疗法。

-2012年11月22日《自然》

中文翻译


【题目】有核红细胞中线粒体Atpif1调控血红素合成

【译文】血红素合成过程中血红素底物的可用性缺陷或者末端转移酶(亚铁鳌合酶,Fech)催化活性的缺陷会损害血红素的合成,因此导致人类先天性贫血。线粒体稳态调控因子的独立功能和负责血红素合成的酶尚不清楚。为了研究这一问题,本研究利用了来自一种深度贫血的石斑鱼pinotage (pnt tq209)的斑马鱼遗传筛选和克隆的线粒体ATP酶抑制因子1(atpif1)。本研究描述了确立Atpif1调控脊椎动物Fech合成血红素的催化效率这一机制。Atpif1的缺失会损害斑马鱼、小鼠和人造血模型中的血红素合成,这是Fech活性减少以及线粒体pH增加的结果。为了理解线粒体pH、氧化还原电位、[2Fe–2S]簇与Fech活性之间的关系,我们利用了pnt中具有或不具有[2Fe–2S] 簇的Fech构成物的遗传互补研究以及调控线粒体pH和氧化还原电位的药物。 [2Fe–2S]簇的出现使得脊椎动物Fech对Atpif1调控的线粒体pH和氧化还原电位中的微扰变得脆弱。因此,Atpif1缺陷会减少脊椎动物Fech合成血红素的效率,引起贫血。线粒体Atpif1作为血红素合成调控因子的鉴定促进我们对调控线粒体血红素稳态及血红细胞发育机制的理解。ATPIF1缺陷可能有助于人类疾病,例如先天性早幼粒细胞性贫血和线粒体病。

英文原稿


[Title]: Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts

[Authors]:Dhvanit I. Shah,1 Naoko Takahashi-Makise,2 Jeffrey D. Cooney,1, 10 Liangtao Li,2 Iman J. Schultz,1, 10 Eric L. Pierce,1, 10 Anupama Narla,1, 3 Alexandra Seguin,2 Dean R. Campagna,8 Carlo Brugnara,9 Yi Zhou,3 Benjamin L. Ebert,1 Nika N. Danial,7 Mark D. Fleming,8 Diane M. Ward,2 Michelangelo Campanella,6 Harry A. Dailey,5 Jerry Kaplan2 & Barry H. Paw1, 3 et al.

[Abstract]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 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt tq209). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 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 Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 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.

原文地址

http://www.nature.com/nature/journal/v491/n7425/full/nature11536.html

 

本站声明: 生物文库所有文章欢迎转载,所有文章未说明,均属于原创,转载均请注明出处。
本文链接: http://www.bioku.cn/201301/nature-mitochondrial-atpif1-erythroblasts-haem-synthesis/
版权所有: 生物文库 - 生物医学、生物技术核心期刊文摘

留言


六 × 8 =


沪ICP备12028140号
点击这里给我发消息   点击这里给我发消息