2012年11月9日 訊 /生物谷BIOON/ --近日，來自布萊根婦女醫(yī)院的研究者發(fā)現(xiàn)了一種新型基因,，其可以在紅細胞形成期間調(diào)節(jié)血紅蛋白的合成,。這項研究發(fā)現(xiàn)刊登在11月7日的國際雜志Nature上，研究發(fā)現(xiàn)可幫助我們增加對生物化學知識的理解以及開發(fā)人類貧血和線粒體障礙的新型療法,。
文章中,，研究者使用了斑馬魚遺傳篩選技術(shù)來克隆線粒體的三磷酸腺苷酶抑制因子-1基因（Atpif1），該基因可使斑馬魚,、小鼠以及人類有效地產(chǎn)生血紅蛋白,，血紅蛋白是血細胞運輸氧氣的重要蛋白質(zhì)。
研究者發(fā)現(xiàn)Atpif1基因的缺失可以促使急性貧血,，而且該基因是調(diào)節(jié)亞鐵螯合酶活性的重要調(diào)節(jié)子,，亞鐵螯合酶是血紅素合成的終端酶。研究者Dhvanit Shah說,，我們的研究揭示了Atpif1基因調(diào)節(jié)線粒體pH,、氧化還原電位2Fe-2S簇，并且結(jié)合至亞鐵螯合酶上調(diào)整血紅素合成之間的關(guān)系,。
最后研究者表示,，發(fā)現(xiàn)Atpif1基因在調(diào)節(jié)血紅素合成上分子機制可以增加我們對體內(nèi)線粒體血紅素平衡以及紅細胞的發(fā)育的理解。這項研究不僅為理解人類先天性貧血，而且也為開發(fā)新型療法提供了很大幫助,。（生物谷Bioon.com）
編譯自：Loss of Essential Blood Cell Gene Leads to Anemia
doi:10.1038/nature11536
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PMID:
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.
