TMEM14C is required for erythroid mitochondrial heme metabolism.
TMEM14C is required for erythroid mitochondrial heme metabolism.
复制标题
DOI：
10.1172/jci76979
复制
发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Yvette Y. Yien;R. Robledo;Iman J. Schultz;Naoko Takahashi‐Makise;B. Gwynn;D. E. Bauer;A. Dass;Gloria Yi;Liangtao Li;G. Hildick-Smith;Jeffrey D. Cooney;E. Pierce;Kyla Mohler;T. Dailey;Non Miyata;P. Kingsley;C. Garone;Shilpa M. Hattangadi;Hui Huang;Wen Chen;E. Keenan;Dhvanit I Shah;T. Schlaeger;S. Dimauro;S. Orkin;A. Cantor;J. Palis;C. Koehler;H. Lodish;J. Kaplan;D. Ward;H. Dailey;J. Phillips;L. Peters;B. Paw
中科院分区：
文献类型：
--
作者：
Yvette Y. Yien;R. Robledo;Iman J. Schultz;Naoko Takahashi‐Makise;B. Gwynn;D. E. Bauer;A. Dass;Gloria Yi;Liangtao Li;G. Hildick-Smith;Jeffrey D. Cooney;E. Pierce;Kyla Mohler;T. Dailey;Non Miyata;P. Kingsley;C. Garone;Shilpa M. Hattangadi;Hui Huang;Wen Chen;E. Keenan;Dhvanit I Shah;T. Schlaeger;S. Dimauro;S. Orkin;A. Cantor;J. Palis;C. Koehler;H. Lodish;J. Kaplan;D. Ward;H. Dailey;J. Phillips;L. Peters;B. Paw
血红素生物合成中间体的运输和细胞内运输对于血红蛋白的产生至关重要，这是红细胞发育的关键过程。在这里，我们分析了终末分化小鼠胎儿肝源性红细胞的基因表达，以确定血红素代谢的调节因子。我们确定TMEM14C是一种线粒体内膜蛋白，在脊椎动物造血组织中富集，对体内和培养的红细胞中的红细胞生成和血红素合成至关重要。在小鼠中，TMEM14C缺乏导致胎儿肝脏卟啉积累，红细胞成熟停止，以及由于深度贫血导致的胚胎死亡。原卟啉IX在tmem14c缺陷红细胞中的合成被阻断，导致卟啉前体的积累。原卟啉IX类似物改善了TMEM14C缺陷细胞的血红素合成缺陷，表明TMEM14C主要在血红素合成途径的末端步骤中起作用。总之，我们的数据表明，TMEM14C促进原卟卟素IX进入线粒体基质，用于血红素合成和随后的血红蛋白生成。此外，TMEM14C作为卟啉原IX输入源的鉴定为进一步探索红细胞生成和先天性贫血提供了遗传学工具。
The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liver-derived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14C-deficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias.