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TMEM14C is required for erythroid mitochondrial heme metabolism
Yvette Y. Yien, … , Luanne L. Peters, Barry H. Paw
Yvette Y. Yien, … , Luanne L. Peters, Barry H. Paw
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4294-4304. https://doi.org/10.1172/JCI76979.
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Research Article Hematology

TMEM14C is required for erythroid mitochondrial heme metabolism

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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.

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

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Figure 2

Tmem14c is specifically required for maturation of the primitive erythroid lineage.

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Tmem14c is specifically required for maturation of the primitive erythro...
(A) Design of Tmem14c gene trap construct (E295C12) used to disrupt expression of Tmem14c. LTR, long term repeat; 6x opn, 6x osteopontin enhancer element; SA, splice acceptor sequence; β-Geo*, β-galactosidase gene fused with the neomycin resistance gene; pA, polyadenylation sequence; UTR, untranslated region. (B) Genomic PCR verifies disruption of Tmem14c locus. (C) Expression of Tmem14c mRNA is abrogated in a Tmem14cgt/gt murine embryonic stem line. (D) The number of hemoglobinized cells is significantly reduced in Tmem14cgt/gt cells, suggesting a defect of erythroid differentiation. (E) Primitive erythroid cells derived from Tmem14cgt/gt embryoid bodies are developmentally arrested at the proerythroblast stage (original magnification, ×60). (F) The number of erythroid colonies formed is decreased in Tmem14cgt/gt derived embryoid bodies. (G) Myeloid lineages derived from embryoid bodies are not affected by Tmem14c deficiency. *P < 0.05.
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