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 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.forename: Yvette Y
authors.initials: YY
authors.lastname: Yien
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Robledo
authors.forename: Iman J
authors.initials: IJ
authors.lastname: Schultz
authors.forename: Naoko
authors.initials: N
authors.lastname: Takahashi-Makise
authors.forename: Babette
authors.initials: B
authors.lastname: Gwynn
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bauer
authors.forename: Abhishek
authors.initials: A
authors.lastname: Dass
authors.forename: Gloria
authors.initials: G
authors.lastname: Yi
authors.forename: Liangtao
authors.initials: L
authors.lastname: Li
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Hildick-Smith
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cooney
authors.forename: Eric L
authors.initials: EL
authors.lastname: Pierce
authors.forename: Kyla
authors.initials: K
authors.lastname: Mohler
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Dailey
authors.forename: Non
authors.initials: N
authors.lastname: Miyata
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kingsley
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.forename: Shilpa M
authors.initials: SM
authors.lastname: Hattangadi
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Keenan
authors.forename: Dhvanit I
authors.initials: DI
authors.lastname: Shah
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Schlaeger
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Alan B
authors.initials: AB
authors.lastname: Cantor
authors.forename: James
authors.initials: J
authors.lastname: Palis
authors.forename: Carla M
authors.initials: CM
authors.lastname: Koehler
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ward
authors.forename: Harry A
authors.initials: HA
authors.lastname: Dailey
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
mesh_terms: D000740:Anemia / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D041905:Erythroid Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006418:Heme / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D008099:Liver / Q000196:embryology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism; D011524:Protoporphyrins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D011166:Porphyrins; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C000595030:TMEM14C protein, mouse; D006418:Heme; C028025:protoporphyrin IX