Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis

Chen, Wen; Dailey, Harry A.; Paw, Barry H.

doi:10.1182/blood-2009-12-259614

Cited by 149 publications

(173 citation statements)

References 24 publications

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“…FECH, the last enzyme in the heme biosynthetic pathway, which catalyzes the insertion of iron into PPIX, forms an oligomeric complex on the inner mitochondrial membrane that include ABCB10 and MITOFERRIN1 (MFRN1). The association of FECH with the mitochondrial iron importer MFRN1 allows the direct transfer of iron to FECH, facilitating heme biosynthesis (22), while ABCB10 plays an important role in the stabilization of MFRN1 expression (23). One intriguing hypothesis is that the mitochondrial heme exporter FLVCR1b represents an additional component of this complex, allowing the direct transfer of heme out of the mitochondrion soon after its synthesis ( Figure 6A).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

Chiabrando

Marro²,

Mercurio³

et al. 2012

J. Clin. Invest.

170

235

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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.

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Section: Discussionmentioning

confidence: 99%

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

Chiabrando

Marro²,

Mercurio³

et al. 2012

J. Clin. Invest.

170

235

View full text Add to dashboard Cite

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“…6 Porin (Calbiochem, San Diego, CA, USA) and a-actin (Novus Biologicals, Littleton, CO, USA) antibodies were used according to manufacturer's instruction. Mfrn1 and BCL-xL (Cell Signalling, Danvers, MA, USA) antibodies were used as previously described 10,23,24 (Supplementary Figure S1).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

et al. 2012

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The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-meÀ/À mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-meÀ/À erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-meÀ/À erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-meÀ/À erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. Cell Death and Differentiation (2012) 19, 1117-1126 doi:10.1038/cdd.2011; published online 13 January 2012A central event during erythroid development is the induction of the components responsible for heme biosynthesis. Although heme is also produced in non-erythroid cells, its biosynthesis is specifically regulated during erythroid differentiation. 1-3 Thus, mutations in some specific genes involved in heme production have been shown to cause several human blood disorders, such as sideroblastic anemias. 4 This type of anemia is characterized by abnormal erythroid differentiation with a reduction in the total number of erythrocytes. 4 In addition, there are idiopathic anemias (either genetic or druginduced) in which the primary molecular defect is unknown. Recently, a novel bioinformatic approach identified new genes involved in heme biosynthesis that could be potential therapeutic targets for these disorders. 5 Furthermore, this large-scale computational screen identified again the ATP Binding Cassette mitochondrial erythroid transporter (ABCme/ABCB10) as an important protein for heme biosynthesis. 5 We previously identified ABC-me as a downstream target of an essential transcription factor for terminal erythroid differentiation, namely GATA-1. 6 ABC-me is a homodimeric transporter located in the inner mitochondrial membrane, which shows the highest expression levels in erythroid tissues. 6,7 Importantly, during early stages of mouse development (day 10 post coitus, pc), ABC-me expression is detected exclusively at the primitive sites of hematopoiesis, namely the yolk sac blood islands. 6 Furthermore, at day 9.5-10.5 pc,...

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“…Non-erythroid cells take up iron into the mitochondria via mitoferrin 1 and its paralogue mitoferrin 2 (SLC25A38) (44). Mitoferrin 1 forms a complex with several proteins, including ferrochelatase and ABCB10 (ATP-binding cassette, subfamily B, member 10), formerly known as ABC-me (45,46). The association of mitoferrin 1 with ferrochelatase, the terminal enzyme in heme synthesis that inserts an iron in protoporphyrin IX to produce heme, likely serves to couple iron transport into the mitochondria to heme biosynthesis.…”

Section: Iron Metabolism In Erythrocyte Precursorsmentioning

confidence: 99%

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

Knutson

2017

Journal of Biological Chemistry

121

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Edited by F. Peter GuengerichCellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease.

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Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis

Abstract: In erythroid cells, ferrous iron is imported into the mitochondrion by mitoferrin-1 (Mfrn1

Cited by 149 publications

References 24 publications

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

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