Erythropoiesis, or the production of red blood cells, is a tightly regulated process that is sensitive to cellular concentrations of heme. The protein FLVCR1 is a heme transporter and mutations in the FLVCR1 gene have been linked to several human diseases, including Diamond-Blackfan anemia, retinitis pigmentosa, and posterior column ataxia. Chiabrando et al. generated Flvcr1 knockout mice to determine the role of different FLVCR1 isoforms in development. Mouse embryos lacking the isoform Flvcr1a exhibited hemorrhages, edema, and skeletal malformations. The panels above show whole mount immunohistochemistry of embryonic mouse tails (top: wt; bottom: Flvcr1a knockout) stained for a protein associated with blood vessels, PECAM. Chiabrando and colleagues determined that the two isoforms of FLVCR1 are involved in distinct steps during erythropoiesis. Misregulation of the two FLVCR1 isoforms could contribute to the pathogenesis of diseases associated with abnormal heme levels.
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.
Deborah Chiabrando, Samuele Marro, Sonia Mercurio, Carlotta Giorgi, Sara Petrillo, Francesca Vinchi, Veronica Fiorito, Sharmila Fagoonee, Annalisa Camporeale, Emilia Turco, Giorgio R. Merlo, Lorenzo Silengo, Fiorella Altruda, Paolo Pinton, Emanuela Tolosano