2012年11月9日 讯 /生物谷BIOON/ --近日，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。这项研究发现刊登在11月7日的国际杂志Nature上，研究发现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。
文章中，研究者使用了斑马鱼遗传筛选技术来克隆线粒体的三磷酸腺苷酶抑制因子-1基因（Atpif1），该基因可使斑马鱼、小鼠以及人类有效地产生血红蛋白，血红蛋白是血细胞运输氧气的重要蛋白质。
研究者发现Atpif1基因的缺失可以促使急性贫血，而且该基因是调节亚铁螯合酶活性的重要调节子，亚铁螯合酶是血红素合成的终端酶。研究者Dhvanit Shah说，我们的研究揭示了Atpif1基因调节线粒体pH、氧化还原电位2Fe-2S簇，并且结合至亚铁螯合酶上调整血红素合成之间的关系。
最后研究者表示，发现Atpif1基因在调节血红素合成上分子机制可以增加我们对体内线粒体血红素平衡以及红细胞的发育的理解。这项研究不仅为理解人类先天性贫血，而且也为开发新型疗法提供了很大帮助。（生物谷Bioon.com）
编译自：Loss of Essential Blood Cell Gene Leads to Anemia
doi:10.1038/nature11536
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Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts
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 et al.
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 anaemias1, 2. 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.
