title: ATP-binding cassette B10 regulates early steps of heme synthesis.
abstract: BACKGROUND
  Heme plays a critical role in gas exchange, mitochondrial energy production, and antioxidant defense in cardiovascular system. The mitochondrial transporter ATP-binding cassette (ABC) B10 has been suggested to export heme out of the mitochondria and is required for normal hemoglobinization of erythropoietic cells and protection against ischemia-reperfusion injury in the heart; however, its primary function has not been established.
  
  
  OBJECTIVE
  The aim of this study was to identify the function of ABCB10 in heme synthesis in cardiac cells.
  
  
  RESULTS
  Knockdown of ABCB10 in cardiac myoblasts significantly reduced heme levels and the activities of heme-containing proteins, whereas supplementation with δ-aminolevulinic acid reversed these defects. Overexpression of mitochondrial δ-aminolevulinic acid synthase 2, the rate-limiting enzyme upstream of δ-aminolevulinic acid export, failed to restore heme levels in cells with ABCB10 downregulation. ABCB10 and heme levels were increased by hypoxia, and reversal of ABCB10 upregulation caused oxidative stress and cell death. Furthermore, ABCB10 knockdown in neonatal rat cardiomyocytes resulted in a significant delay of calcium removal from the cytoplasm, suggesting a relaxation defect. Finally, ABCB10 expression and heme levels were altered in failing human hearts and mice with ischemic cardiomyopathy.
  
  
  CONCLUSIONS
  ABCB10 plays a critical role in heme synthesis pathway by facilitating δ-aminolevulinic acid production or export from the mitochondria. In contrast to previous reports, we show that ABCB10 is not a heme exporter and instead is required for the early mitochondrial steps of heme biosynthesis.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: Marina
authors.initials: M
authors.lastname: Bayeva
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Burke
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: Neha
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Medicine, Obesity and Nutrition Section, Mitochondria ARC, Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany St., Boston, MA 02118, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Department of Medicine, Obesity and Nutrition Section, Mitochondria ARC, Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany St., Boston, MA 02118, USA.
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.affiliation: Hematology Division, Brigham & Women's Hospital; Hematology-Oncology Division, Children's Hospital Boston; Harvard Medical School, Boston, MA.
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Langer
authors.affiliation: Hematology Division, Brigham & Women's Hospital; Hematology-Oncology Division, Children's Hospital Boston; Harvard Medical School, Boston, MA.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL.
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D006418:Heme / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats
chemical_list: C412459:ABCB10 protein, human; D018528:ATP-Binding Cassette Transporters; D006418:Heme
keywords: ATP-binding cassette transporters; cardiomyopathies; heme; mitochondria; δ-aminolevulinic acid