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.
Yvette Y. Yien, Raymond F. Robledo, Iman J. Schultz, Naoko Takahashi-Makise, Babette Gwynn, Daniel E. Bauer, Abhishek Dass, Gloria Yi, Liangtao Li, Gordon J. Hildick-Smith, Jeffrey D. Cooney, Eric L. Pierce, Kyla Mohler, Tamara A. Dailey, Non Miyata, Paul D. Kingsley, Caterina Garone, Shilpa M. Hattangadi, Hui Huang, Wen Chen, Ellen M. Keenan, Dhvanit I. Shah, Thorsten M. Schlaeger, Salvatore DiMauro, Stuart H. Orkin, Alan B. Cantor, James Palis, Carla M. Koehler, Harvey F. Lodish, Jerry Kaplan, Diane M. Ward, Harry A. Dailey, John D. Phillips, Luanne L. Peters, Barry H. Paw
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. All accepted letters will be posted on our website within one week of acceptance. We reserve the right to edit any letter for length, content, and clarity. Authors of all accepted letters will be asked to preview any changes. Authors will be notified by e-mail if their letters were not accepted. As this is a final decision, no appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at firstname.lastname@example.org.