1. TMEM14C is required for erythroid mitochondrial heme metabolism
- Author
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Abhishek Dass, Eric A. Pierce, Daniel E. Bauer, Dhvanit I. Shah, Salvatore DiMauro, Barry H. Paw, Jeffrey D. Cooney, Hui Huang, Tamara A. Dailey, Naoko Takahashi-Makise, John Gary Phillips, Kyla Mohler, Yvette Y. Yien, Paul D. Kingsley, Thorsten M. Schlaeger, Harvey F. Lodish, Raymond F. Robledo, Wen Chen, Diane M. Ward, Stuart H. Orkin, Caterina Garone, Carla M. Koehler, Ellen M. Keenan, Iman J. Schultz, Gloria Yi, James Palis, Shilpa M. Hattangadi, Luanne L. Peters, Non Miyata, Jerry Kaplan, Alan B. Cantor, Babette Gwynn, Liangtao Li, Harry A. Dailey, Gordon J. Hildick-Smith, Yien Y.Y., Robledo R.F., Schultz I.J., Takahashi-Makise N., Gwynn B., Bauer D.E., Dass A., Yi G., Li L., Hildick-Smith G.J., Cooney J.D., Pierce E.L., Mohler K., Dailey T.A., Miyata N., Kingsley P.D., Garone C., Hattangadi S.M., Huang H., Chen W., Keenan E.M., Shah D.I., Schlaeger T.M., Dimauro S., Orkin S.H., Cantor A.B., Palis J., Koehler C.M., Lodish H.F., Kaplan J., Ward D.M., Dailey H.A., Phillips J.D., Peters L.L., and Paw B.H.
- Subjects
Protoporphyrins ,Medical and Health Sciences ,Mitochondrial Membrane Transport Proteins ,chemistry.chemical_compound ,Hemoglobins ,Mice ,0302 clinical medicine ,Erythropoiesi ,Erythropoiesis ,RNA, Small Interfering ,Inner mitochondrial membrane ,Membrane Protein ,0303 health sciences ,Protoporphyrin IX ,Liver Disease ,Anemia ,General Medicine ,Hematology ,Protoporphyrin ,Protoporphyrinogen IX ,Mitochondria ,Biochemistry ,Liver ,Mitochondrial matrix ,030220 oncology & carcinogenesis ,Mitochondrial Membranes ,Intracellular ,Research Article ,Porphyrins ,Immunology ,Heme ,Biology ,Small Interfering ,Cell Line ,Porphyrin ,03 medical and health sciences ,Erythroid Cells ,Animals ,Hemoglobin ,030304 developmental biology ,Erythroid Cell ,Animal ,Membrane Proteins ,Mitochondrial Membrane Transport Protein ,chemistry ,Gene Expression Regulation ,RNA ,Mitochondrial Membrane ,Digestive Diseases - Abstract
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.
- Published
- 2014