title: The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation.
abstract: Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a cell membrane heme exporter that maintains the balance between heme levels and globin synthesis in erythroid precursors. It was previously shown that Flvcr1-null mice died in utero due to a failure of erythropoiesis. Here, we identify Flvcr1b, a mitochondrial Flvcr1 isoform that promotes heme efflux into the cytoplasm. Flvcr1b overexpression promoted heme synthesis and in vitro erythroid differentiation, whereas silencing of Flvcr1b caused mitochondrial heme accumulation and termination of erythroid differentiation. Furthermore, mice lacking the plasma membrane isoform (Flvcr1a) but expressing Flvcr1b had normal erythropoiesis, but exhibited hemorrhages, edema, and skeletal abnormalities. Thus, FLVCR1b regulates erythropoiesis by controlling mitochondrial heme efflux, whereas FLVCR1a expression is required to prevent hemorrhages and edema. The aberrant expression of Flvcr1 isoforms may play a role in the pathogenesis of disorders characterized by an imbalance between heme and globin synthesis.
authors.affiliation: Molecular Biotechnology Centre, Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Chiabrando
authors.forename: Samuele
authors.initials: S
authors.lastname: Marro
authors.forename: Sonia
authors.initials: S
authors.lastname: Mercurio
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.forename: Sara
authors.initials: S
authors.lastname: Petrillo
authors.forename: Francesca
authors.initials: F
authors.lastname: Vinchi
authors.forename: Veronica
authors.initials: V
authors.lastname: Fiorito
authors.forename: Sharmila
authors.initials: S
authors.lastname: Fagoonee
authors.forename: Annalisa
authors.initials: A
authors.lastname: Camporeale
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Giorgio R
authors.initials: GR
authors.lastname: Merlo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tolosano
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation; D004487:Edema / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism / Q000502:physiology*; D004920:Erythropoiesis; D005091:Exons; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006418:Heme / Q000378:metabolism; D006470:Hemorrhage / Q000235:genetics; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D011991:Receptors, Virus; D006418:Heme