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The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation
Deborah Chiabrando, … , Paolo Pinton, Emanuela Tolosano
Deborah Chiabrando, … , Paolo Pinton, Emanuela Tolosano
Published November 26, 2012
Citation Information: J Clin Invest. 2012;122(12):4569-4579. https://doi.org/10.1172/JCI62422.
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Research Article

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

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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

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

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Figure 2

FLVCR1b overexpression increases intracellular heme content, while its silencing results in heme accumulation in mitochondria.

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FLVCR1b overexpression increases intracellular heme content, while its s...
(A) Heme levels in HeLa cells overexpressing FLVCR1a-myc, FLVCR1b-myc, or a control vector. Succinylacetone was used as a competitive inhibitor of heme biosynthesis. n = 6. Two-way ANOVA. (B and C) qRT-PCR analysis of Ho-1 mRNA and Alas1 mRNA in FLVCR1b-overexpressing HeLa cells compared with control. n = 6. t test. (D and E) Heme content and qRT-PCR analysis of Ho-1 transcript levels in HeLa cells in which the expression of both FLVCR1a and FLVCR1b, or FLVCR1a alone, was downregulated using specific shRNA. Heme biosynthesis was stimulated with ALA. n = 6. Two-way ANOVA. (F) Heme content in mitochondria and cytosol from HeLa cells, in which the expression of both FLVCR1a and FLVCR1b, or FLVCR1a alone, was downregulated using specific shRNA compared with control cells. n = 6. One-way ANOVA. (G) Heme content in mitochondria and cytosol isolated from HeLa cells in which FLVCR1b expression was downregulated using a specific siRNA against the 5′ UTR of Flvcr1b with respect to controls. n = 6. Two-way ANOVA. (H) Quantity of cytochrome c oxidase in control versus silenced FLVCR1a-b HeLa cells. n = 4. (I) Mitochondrial Ca2+ responses to agonist stimulation in control and silenced FVLCR1a-b HeLa cells. Data were normalized to mean of the control group. Traces are representative of 12 experiments from 3 preparations. t test. Values represent mean ± SEM. *P < 0.05; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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