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 Chen & 15 others 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

研究成果: ジャーナルへの寄稿記事

25 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)4294-4304
ページ数11
ジャーナルJournal of Clinical Investigation
124
発行部数10
DOI
出版物ステータス出版済み - 10 1 2014

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Heme
Erythroid Cells
Erythropoiesis
Porphyrins
Anemia
Hemoglobins
Mitochondrial Proteins
Mitochondrial Membranes
Vertebrates
Cultured Cells
Membrane Proteins
Gene Expression
Liver

All Science Journal Classification (ASJC) codes

  • Medicine(all)

これを引用

Yien, Y. Y., Robledo, R. F., Schultz, I. J., Takahashi-Makise, N., Gwynn, B., Bauer, D. E., ... Paw, B. H. (2014). TMEM14C is required for erythroid mitochondrial heme metabolism. Journal of Clinical Investigation, 124(10), 4294-4304. https://doi.org/10.1172/JCI76979

TMEM14C is required for erythroid mitochondrial heme metabolism. / Yien, Yvette Y.; Robledo, Raymond F.; Schultz, Iman J.; Takahashi-Makise, Naoko; Gwynn, Babette; Bauer, Daniel E.; Dass, Abhishek; Yi, Gloria; Li, Liangtao; Hildick-Smith, Gordon J.; Cooney, Jeffrey D.; Pierce, Eric L.; Mohler, Kyla; Dailey, Tamara A.; Miyata, Non; Kingsley, Paul D.; Garone, Caterina; Hattangadi, Shilpa M.; Huang, Hui; Chen, Wen; Keenan, Ellen M.; Shah, Dhvanit I.; Schlaeger, Thorsten M.; Dimauro, Salvatore; Orkin, Stuart H.; Cantor, Alan B.; Palis, James; Koehler, Carla M.; Lodish, Harvey F.; Kaplan, Jerry; Ward, Diane M.; Dailey, Harry A.; Phillips, John D.; Peters, Luanne L.; Paw, Barry H.

:: Journal of Clinical Investigation, 巻 124, 番号 10, 01.10.2014, p. 4294-4304.

研究成果: ジャーナルへの寄稿記事

Yien, YY, Robledo, RF, Schultz, IJ, Takahashi-Makise, N, Gwynn, B, Bauer, DE, Dass, A, Yi, G, Li, L, Hildick-Smith, GJ, Cooney, JD, Pierce, EL, Mohler, K, Dailey, TA, Miyata, N, Kingsley, PD, Garone, C, Hattangadi, SM, Huang, H, Chen, W, Keenan, EM, Shah, DI, Schlaeger, TM, Dimauro, S, Orkin, SH, Cantor, AB, Palis, J, Koehler, CM, Lodish, HF, Kaplan, J, Ward, DM, Dailey, HA, Phillips, JD, Peters, LL & Paw, BH 2014, 'TMEM14C is required for erythroid mitochondrial heme metabolism', Journal of Clinical Investigation, 巻. 124, 番号 10, pp. 4294-4304. https://doi.org/10.1172/JCI76979
Yien YY, Robledo RF, Schultz IJ, Takahashi-Makise N, Gwynn B, Bauer DE その他. TMEM14C is required for erythroid mitochondrial heme metabolism. Journal of Clinical Investigation. 2014 10 1;124(10):4294-4304. https://doi.org/10.1172/JCI76979
Yien, Yvette Y. ; Robledo, Raymond F. ; Schultz, Iman J. ; Takahashi-Makise, Naoko ; Gwynn, Babette ; Bauer, Daniel E. ; Dass, Abhishek ; Yi, Gloria ; Li, Liangtao ; Hildick-Smith, Gordon J. ; Cooney, Jeffrey D. ; Pierce, Eric L. ; Mohler, Kyla ; Dailey, Tamara A. ; Miyata, Non ; Kingsley, Paul D. ; Garone, Caterina ; Hattangadi, Shilpa M. ; Huang, Hui ; Chen, Wen ; Keenan, Ellen M. ; Shah, Dhvanit I. ; Schlaeger, Thorsten M. ; Dimauro, Salvatore ; Orkin, Stuart H. ; Cantor, Alan B. ; Palis, James ; Koehler, Carla M. ; Lodish, Harvey F. ; Kaplan, Jerry ; Ward, Diane M. ; Dailey, Harry A. ; Phillips, John D. ; Peters, Luanne L. ; Paw, Barry H. / TMEM14C is required for erythroid mitochondrial heme metabolism. :: Journal of Clinical Investigation. 2014 ; 巻 124, 番号 10. pp. 4294-4304.
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title = "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 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.",
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T1 - TMEM14C is required for erythroid mitochondrial heme metabolism

AU - Yien, Yvette Y.

AU - Robledo, Raymond F.

AU - Schultz, Iman J.

AU - Takahashi-Makise, Naoko

AU - Gwynn, Babette

AU - Bauer, Daniel E.

AU - Dass, Abhishek

AU - Yi, Gloria

AU - Li, Liangtao

AU - Hildick-Smith, Gordon J.

AU - Cooney, Jeffrey D.

AU - Pierce, Eric L.

AU - Mohler, Kyla

AU - Dailey, Tamara A.

AU - Miyata, Non

AU - Kingsley, Paul D.

AU - Garone, Caterina

AU - Hattangadi, Shilpa M.

AU - Huang, Hui

AU - Chen, Wen

AU - Keenan, Ellen M.

AU - Shah, Dhvanit I.

AU - Schlaeger, Thorsten M.

AU - Dimauro, Salvatore

AU - Orkin, Stuart H.

AU - Cantor, Alan B.

AU - Palis, James

AU - Koehler, Carla M.

AU - Lodish, Harvey F.

AU - Kaplan, Jerry

AU - Ward, Diane M.

AU - Dailey, Harry A.

AU - Phillips, John D.

AU - Peters, Luanne L.

AU - Paw, Barry H.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

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U2 - 10.1172/JCI76979

DO - 10.1172/JCI76979

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