Year: 2014
Type: article
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.
DOI: 10.1172/jci76979
Authors: 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
Institutions: Brigham and Women's Hospital, Harvard University, Jackson Laboratory, University of Utah, Boston Children's Hospital, Dana-Farber Cancer Institute, Cornell University, The University of Texas at San Antonio, Georgia Institute of Technology, University of Georgia, University of California, Los Angeles, University of Rochester Medicine, University of Rochester, Columbia University, Yale University, Whitehead Institute for Biomedical Research, Texas A&M University, Columbia University Irving Medical Center, Massachusetts Institute of Technology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: March of Dimes Foundation, American Heart Association, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Harvard Digestive Diseases Center, Harvard University, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G147635816, G1485557932, G1573172102, G164861384, G1863849263, PORPHYRIN BIOSYNTHESIS IN NORMAL AND DISEASE STATES, G2524381298, G2564359619, G2782235213, G278894908, G2793605890, G3613222656, DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS, G494583905, G4966714121, Frascati: mitochondrial transporter and erythropoiesis, G5208121238, G5228971872, G599701834, Porphyrin biosynthesis in normal and disease states, G6363704104, G6422630283, Genetic Identification of Novel Genes Critical in Erythropoiesis, G7080714740, G7533489540, G8344923774, G9000044143, G9000049628, G9000090970, G9000092807, G9000148405, G9000188916, G9000197162, G9000313661, BIOGENESIS OF THE MITOCHONDRIAL INNER MEMBRANE, Integrated Epithelial and Muscosal Biology, G965315884
OpenAlex ID: W2014702774