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 October 1, 2014; First published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4294-4304. https://doi.org/10.1172/JCI76979.
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Categories: Research Article Hematology

TMEM14C is required for erythroid mitochondrial heme metabolism

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 5

TMEM14C is not required for mitochondrial iron homeostasis.

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TMEM14C is not required for mitochondrial iron homeostasis. (A) Quantita...
(A) Quantitation of cellular iron status by 55Fe metabolic labeling shows that basal cellular iron import is not decreased in Tmem14c-deficient MEL cells. However, cellular iron content is decreased in Tmem14c-deficient erythroid cells during differentiation. (B) Deficiency in heme synthesis in Tmem14c-silenced cells is not due to a defect in mitochondrial iron content. Inductively coupled plasma analysis of mitochondrial iron shows that Tmem14c deficiency does not cause a defect in mitochondrial iron content either basally or during erythroid differentiation (left). This was confirmed by 59Fe metabolic labeling and quantitation of mitochondrial iron from differentiating Tmem14c-silenced cells (right). (C) Normal activities for [2Fe-2S] cofactor–dependent mitochondrial aconitase, FECH, and cytosolic xanthine oxidase in Tmem14c-silenced cells exclude defects in [2Fe-2S] cluster assembly. *P < 0.05.