TMEM14C is required for erythroid mitochondrial heme metabolism

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 ChenEllen 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

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)


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 liverderived 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.

Original languageEnglish
Pages (from-to)4294-4304
Number of pages11
JournalJournal of Clinical Investigation
Issue number10
Publication statusPublished - Oct 1 2014

All Science Journal Classification (ASJC) codes

  • General Medicine


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