Fam210b Is Required for Optimal Cellular and Mitochondrial Iron Uptake during Erythroid Differentiation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 405-405
Author(s):  
Yvette Y Yien ◽  
Caiyong Chen ◽  
Jiahai Shi ◽  
Liangtao Li ◽  
Daniel E. Bauer ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Aminolevulinic Acid ◽  
Genetic Modifier ◽  
Terminal Differentiation ◽  
Erythroid Differentiation ◽  
Hemoglobin Synthesis ◽  
Heme Synthesis ◽  
Mitochondrial Iron ◽  
Murine Erythroleukemia

Abstract Red cells synthesize large quantities of heme during terminal differentiation. Central to erythropoiesis is the transport and trafficking of iron within the cell. Despite the importance of iron transport during erythroid heme synthesis, the molecules involved in intracellular trafficking of iron are largely unknown. In a screen for genes that are up-regulated during erythroid terminal differentiation, we identified FAM210B, a predicted multi-pass transmembrane mitochondrial protein as an essential component of mitochondrial iron transport during erythroid differentiation. In zebrafish and mice, Fam210b mRNA is enriched in differentiating erythroid cells and liver (fetal and adult), which are tissues that require large amounts of iron for heme synthesis. Here, we report that FAM210B facilitates mitochondrial iron import during erythroid differentiation and is essential for hemoglobin synthesis. Zebrafish are anemic when fam210b is silenced using anti-sense morpholinos (Fig. A). CRISPR knockout of Fam210b caused a heme synthesis defect in differentiating Friend murine erythroleukemia (MEL) cells. PPIX levels in Fam210b deficient cells are normal, demonstrating that Fam210b does not participate in synthesis of the heme tetrapyrrole ring. Consistent with this result, supplementation of Fam210b deficient MEL cells with either aminolevulinic acid, the first committed substrate of the heme synthesis pathway or a chemical analog of protoporphyrin IX failed to chemically complement the heme synthesis defect. While Fam210b was not required for basal housekeeping heme synthesis, Fam210b deficientcells showed defective total cellular and mitochondrial iron uptake during erythroid differentiation (Fig. B). As a result, Fam210b deficient cells had defective hemoglobinization. Supplementation of Fam210b-/- MEL cells with non-transferrin iron chelates restored erythroid differentiation and hemoglobin synthesis; whereas, similar chemical complementation could not be achieved in the Tmem14c-/- cells, which have a primary defect in tetrapyrrole transport. (Fig. C). Our findings reveal that FAM210B is required for optimal mitochondrial iron import during erythroid differentiation for hemoglobin synthesis. It may therefore function as a genetic modifier for mitochondriopathies, anemias or porphyrias. Figure 1. Figure 1. Disclosures Bauer: Biogen: Research Funding; Editas Medicine: Consultancy. Orkin:Editas Inc.: Consultancy.

scholarly journals Iron distribution in Belgrade rat reticulocytes after inhibition of heme synthesis with succinylacetone

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3414-3421 ◽  
Author(s):  
LM Garrick ◽  
K Gniecko ◽  
Y Liu ◽  
DS Cohan ◽  
JA Grasso ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Aminolevulinic Acid ◽  
Specific Inhibitor ◽  
Hypochromic Anemia ◽  
Endocytic Vesicle ◽  
Heme Synthesis ◽  
Diferric Transferrin ◽  
Rat Reticulocytes ◽  
Insight Into

Abstract We have used succinylacetone (4,6-dioxoheptanoic acid), a specific inhibitor of delta-aminolevulinic acid dehydrase, to gain insight into the defect in iron metabolism in the Belgrade anemia. The Belgrade rat has an inherited microcytic, hypochromic anemia associated with poor iron uptake into developing erythroid cells. Succinylacetone inhibits heme synthesis, leading to nonheme iron accumulation in mitochondria and cytosol of normal reticulocytes. When succinylacetone is used to inhibit Belgrade heme synthesis, iron from diferric transferrin does not accumulate in the stromal fraction that contains mitochondria, nor does 59Fe accumulate in the nonheme cytosolic fraction. Hence, the defect in the Belgrade rat reticulocyte occurs in the endocytic vesicle or in a step subsequent to iron transit from the vesicle but before the nonheme cytosolic or mitochondrial iron fractions. Therefore, the mutation affects either the release of iron from transferrin or iron transport from the vesicle to the mitochondrion.

Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2575-2583 ◽  
Author(s):  
Khalid Hafid-Medheb ◽  
Yvette Augery-Bourget ◽  
Marie-Nathalie Minatchy ◽  
Nicole Hanania ◽  
Jacqueline Robert-Lézénès
Keyword(s):  
Erythroid Differentiation ◽  
Erythroid Cells ◽  
Chemical Induction ◽  
Globin Mrna ◽  
Antisense Transcripts ◽  
Hemoglobin Synthesis ◽  
Heme Synthesis ◽  
Mrna Induction ◽  
Before And After ◽  
Murine Erythroleukemia

Bcl-XL is essential for the survival and normal maturation of erythroid cells, especially at the late stage of erythroid differentiation. It remains unclear whether Bcl-XL serves only as a survival factor for erythroid cells or if it can induce a signal for differentiation. We have previously shown that dimethyl sulfoxide (DMSO) induction of erythroid differentiation in murine erythroleukemia (MEL) cells correlates with delay of apoptosis and specific induction of Bcl-XL. In this study, we investigate the contribution of Bcl-2 and Bcl-XL to survival and erythroid differentiation by generating stable MEL transfectants expressing these antiapoptotic regulators. Overexpression of Bcl-2 completely prevented apoptosis of MEL cells before and after DMSO induction, whereas overexpression of Bcl-XL only delayed it. Overexpression of Bcl-2 or Bcl-XL neither induced spontaneous erythroid differentiation nor accelerated DMSO-induced differentiation. Inhibition of Bcl-XL by antisense transcripts accelerated apoptosis in DMSO-treated MEL cells and blocked the synthesis of hemoglobin without altering the growth arrest associated with terminal erythroid differentiation. An antisense oligonucleotide to Bcl-XL did not induce apoptosis in MEL cells overexpressing Bcl-2 but greatly decreased their hemoglobin synthesis when treated with DMSO, suggesting that Bcl-XL is necessary for erythroid differentiation independently of its antiapoptotic function. Importantly, Bcl-XL antisense transcripts prevented heme synthesis but not globin mRNA induction in DMSO-treated MEL cells. Furthermore, inhibition of hemoglobin synthesis by Bcl-XLantisense was reversed by addition of exogenous hemin. Finally, Bcl-XL localized to mitochondria during MEL erythroid differentiation, suggesting that it may mediate a critical mitochondrial transport function related to heme biosynthesis.

scholarly journals Iron distribution in Belgrade rat reticulocytes after inhibition of heme synthesis with succinylacetone

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3414-3421 ◽  
Author(s):  
LM Garrick ◽  
K Gniecko ◽  
Y Liu ◽  
DS Cohan ◽  
JA Grasso ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Aminolevulinic Acid ◽  
Specific Inhibitor ◽  
Hypochromic Anemia ◽  
Endocytic Vesicle ◽  
Heme Synthesis ◽  
Diferric Transferrin ◽  
Rat Reticulocytes ◽  
Insight Into

We have used succinylacetone (4,6-dioxoheptanoic acid), a specific inhibitor of delta-aminolevulinic acid dehydrase, to gain insight into the defect in iron metabolism in the Belgrade anemia. The Belgrade rat has an inherited microcytic, hypochromic anemia associated with poor iron uptake into developing erythroid cells. Succinylacetone inhibits heme synthesis, leading to nonheme iron accumulation in mitochondria and cytosol of normal reticulocytes. When succinylacetone is used to inhibit Belgrade heme synthesis, iron from diferric transferrin does not accumulate in the stromal fraction that contains mitochondria, nor does 59Fe accumulate in the nonheme cytosolic fraction. Hence, the defect in the Belgrade rat reticulocyte occurs in the endocytic vesicle or in a step subsequent to iron transit from the vesicle but before the nonheme cytosolic or mitochondrial iron fractions. Therefore, the mutation affects either the release of iron from transferrin or iron transport from the vesicle to the mitochondrion.

Studies on Heme Oxygenase 1 During Erythroid Differentiation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4254-4254
Author(s):  
Daniel Garcia Santos ◽  
Jesse Eisenberg ◽  
Matthias Schranzhofer ◽  
Prem Ponka
Keyword(s):  
Aminolevulinic Acid ◽  
Conflicts Of Interest ◽  
Tissue Injury ◽  
Erythroid Differentiation ◽  
The Body ◽  
Cellular Damage ◽  
Erythroid Cell ◽  
Heme Oxygenase 1 ◽  
Erythroid Cells ◽  
Murine Erythroleukemia

Abstract Abstract 4254 Heme is indispensable for the function of all aerobic cells as a prosthetic group of innumerable proteins. However, “free heme” (uncommitted) can initiate the formation of free radicals and cause lipid peroxidation, which can lead to cellular damage and tissue injury. Therefore, the rate of heme biosynthesis and catabolism must be well balanced by tight control mechanisms. The highest amounts of organismal heme (75-80%) are present in circulating red blood cells (RBC), whose precursors synthesize heme with rates that are at least one order of magnitude higher (on the per cell basis) than those in the liver – the second most active heme producer in the body. The degradation of heme is exclusively carried out by heme oxygenases 1 and 2 (HO1 and HO2), which catalyze the rate-limiting step in the oxidative degradation of heme. Although the heme-inducible HO isoform, HO1, has been extensively studied in hepatocytes and many other non-erythroid cells, virtually nothing is known about the expression of HO1 in developing RBC. Similarly, it is unknown whether HO1 plays any role in erythroid cell development under physiological or pathophysiological conditions. Using both a murine erythroleukemia cell line (MEL) and primary erythroid cells isolated from mouse fetal livers, we have demonstrated that during erythroid differentiation HO1 is up-regulated at both mRNA and protein levels. This increase in HO1 can be prevented by succinylacetone (SA), an inhibitor of heme synthesis that blocks 5-aminolevulinic acid dehydratase. These data suggest that in developing RBC, in addition to the continuous assembly of heme with globin chains, there is an increase in levels of uncommitted heme, which upregulates HO1 expression. Additionally, we have shown that down-regulation of HO1 via siRNA increased hemoglobinization in differentiating MEL cells. In contrast, induction of HO1 expression by NaAsO2 reduced the hemoglobinization of MEL cells. This effect could be reversed to control levels by the addition of HO1 inhibitor tin-protophorphyrin (SnPP). These results show that in differentiating erythroid cells the balance between levels of heme and HO1 have to be tightly regulated to maintain hemoglobinization at appropriate levels. Our results lead us to propose that disturbances in HO1 expression could play a role in some pathophysiological conditions such as thalassemias. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of hemoglobin synthesis by downregulation of MYB protein with an antisense oligodeoxynucleotide

Blood ◽  
1991 ◽  
Vol 78 (4) ◽  
pp. 991-996 ◽  
Author(s):  
YJ Chern ◽  
C O'Hara ◽  
AJ Sytkowski
Keyword(s):  
Plasma Membrane ◽  
Terminal Differentiation ◽  
Erythroid Differentiation ◽  
Anion Transport ◽  
Transport Protein ◽  
Antisense Oligodeoxynucleotide ◽  
Hemoglobin Synthesis ◽  
Chemical Agents ◽  
Erythroleukemia Cells ◽  
Myb Protein

Abstract Reduced expression of the proto-oncogene c-myb appears necessary for erythroid differentiation induced by chemical agents and by the natural regulator, erythropoietin (Epo). Treatment of Epo-responsive Rauscher erythroleukemia cells with an anti-sense oligodeoxynucleotide to c-myb in the absence of other inducers downregulated myb protein markedly and caused hemoglobinization of the cells within 48 hours. Epo treatment, which downregulates c-myb in these cells, induced hemoglobinization to the same degree. Epo also induced the appearance of anion transport protein on the plasma membrane, consistent with terminal differentiation. In contrast, antisense c-myb did not induce this erythroid marker. The results are consistent with a role for myb protein in the regulation of hemoglobin synthesis.

scholarly journals Precommitted erythroid cells enriched in cultures of suboptimally induced Friend erythroleukemia cells

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1565-1571
Author(s):  
E DiMambro ◽  
M Galanti ◽  
SB Levy
Keyword(s):  
Protein Synthesis ◽  
Rna Synthesis ◽  
Terminal Differentiation ◽  
Metabolic Inhibitors ◽  
Hemoglobin Synthesis ◽  
Erythroleukemia Cells ◽  
Chemically Induced ◽  
Primed Cell ◽  
Murine Erythroleukemia ◽  
New Protein

Abstract In the presence of suboptimal inducing amounts of dimethylsulfoxide or hexamethylenebisacetamide, a major proportion of uncommitted murine erythroleukemia (MEL) cells was found to be precommitted or primed for commitment, which was demonstrated by their rapid commitment to terminal differentiation when recultured for short periods of time (three to six hours) with fresh inducer. These same cells did not commit if left in the original inducer-containing media or if replated in fresh media without inducer. The two inducers could be interchanged in the priming and postpriming period without affecting the commitment event. However, hemin, an agent that induces hemoglobin synthesis without commitment, showed no ability to enhance commitment of a primed cell population. The rapid commitment of primed cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate and cordycepin but not by cycloheximide. The latter finding indicated that this rapid inducer- dependent commitment event required new RNA synthesis but not new protein synthesis. The precommitment state was lost within six hours of the growth of cells in the absence of inducer but could be sustained longer if cells were incubated in cycloheximide. These studies characterize a precommitment state not previously described and one that appears during chemically induced differentiation in the absence of metabolic inhibitors. The stabilization of these precommitted cells by cycloheximide suggests that the reversibility of precommitment involves new protein synthesis. These findings show that MEL cells proceed to terminal differentiation by accumulating unstable products that must be maintained by the inducer until the final commitment event.

Tmem14c Plays An Essential Role In Mitochondrial Heme Metabolism

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 427-427 ◽  
Author(s):  
Barry H. Paw ◽  
Yvette Y. Yien ◽  
Raymond F Robledo ◽  
Iman J. Schultz ◽  
Naoko Takahashi-Makise ◽  
...  
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Transmembrane Protein ◽  
Protoporphyrin Ix ◽  
Terminal Differentiation ◽  
Gene Trap ◽  
Erythroid Cells ◽  
Coproporphyrinogen Oxidase ◽  
Heme Synthesis ◽  
Murine Erythroleukemia

Abstract Red cells synthesize large amounts of heme during terminal differentiation. Central to this process is the transport and trafficking of heme synthesis intermediates within the cell. Despite the importance of transport during heme synthesis, the molecules involved in this process are largely unknown. In a screen for genes that are upregulated during erythroid terminal differentiation, we identified Tmem14c, a predicted multi-pass transmembrane protein as an essential component of the porphyrin metabolism pathway. Here, we report that Tmem14c facilitates the synthesis of mitochondrial protoporphyrin IX from coproporphyrinogen III and is thus required for heme synthesis. Tmem14c is a mitochondrial inner-membrane protein enriched in vertebrate hematopoietic tissues and is required for terminal erythropoiesis. Tmem14c gene-trap mouse embryos are severely anemic and mostly die by E13.5 (Fig. A). Fetal liver erythroid cells derived from gene-trap embryos experience maturation arrest. shRNA silencing of Tmem14c in Friend murine erythroleukemia (MEL) cells results in a significant decrease in de-novo heme synthesis. The biochemical defect is due to a decrease in mitochondrial protoporphyrin IX synthesis, while cytoplasmic porphyrin levels remain normal (Fig. B). The heme synthesis defect in Tmem14c-silenced MEL cells is complemented with a protoporphyrin IX analog. These data show the role of Tmem14c in regulating the terminal steps in mitochondrial porphyrin trafficking. Our findings collectively demonstrate that Tmem14c is required for the transport of mitochondrial porphyrins in developing erythroid cells. Due to its inner-mitochondrial localization and its relative proximity to heme synthetic enzymes coproporphyrinogen oxidase and protoporphyrinogen oxidase (Rhee et al., 2013 Science), Tmem14c can function as a molecular adaptor that facilitates the interaction of proteins involved in porphyrin transport, or as a protoporphyrinogen IX transporter (Fig. C). The identification of Tmem14c as an essential regulator of porphyrin transport and heme synthesis provides a novel genetic tool for exploring erythropoiesis and disorders of heme synthesis such as porphyria and anemia. Disclosures: No relevant conflicts of interest to declare.

The Interplay of GATA1 with Heme Regulates an Erythroid Cell's Differentiation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 541-541
Author(s):  
Raymond T Doty ◽  
Xiaowei Yan ◽  
Christopher Lausted ◽  
Zhantao Yang ◽  
Li Liu ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Aminolevulinic Acid ◽  
Macrocytic Anemia ◽  
Erythroid Differentiation ◽  
Gene Set Enrichment Analysis ◽  
Erythroid Cells ◽  
Ineffective Erythropoiesis ◽  
P53 Pathway ◽  
Heme Synthesis ◽  
Marrow Cells

Abstract GATA1 promotes the transcription of ALAS2, the first and rate limiting step of heme synthesis, and the transcription of many other erythroid-specific genes. It also increases its own transcription while silencing proliferation genes active in early progenitors and thus assures that erythroid differentiation correctly initiates. Heme then transcriptionally and translationally upregulates globin to guarantee adequate hemoglobin production in each cell as it matures. In mice lacking the heme exporter, FLVCR1, excess heme and ROS accumulate and erythropoiesis fails at the CFU-E/proerythroblast stage, resulting in a severe macrocytic anemia (HGB 4.4±0.97 vs 14.8±0.57 g/dL; MCV 66.9±6.2 vs 48.4±0.65 fL). To determine how excess heme causes ineffective erythropoiesis and whether heme is key to terminating differentiation in normal erythroid cells, we performed RNA sequencing of single early erythroid cells (BFU-E to basophilic erythroblasts) from wildtype control and Flvcr1-deleted mice and linked this transcription data to the total quantity of Ter119 on that cell. Principal component analysis (PCA) identified 4 transcriptionally unique clusters A, B, C, & D, which contained cells with negative, low, intermediate, and high Ter119 levels respectively. α- and β-globin transcription were highly correlated (r=0.975), occurred in all cells, increased as Ter119 expression increased, and upregulated in Flvcr1-deleted cells. Gene set enrichment analysis (GSEA) comparing control cells to Flvcr1-deleted cells revealed excess heme results in significant downregulation of the hallmark heme metabolism pathway genes (heme biosynthesis and erythroid differentiation genes), upregulation of the ribosome pathway genes, and no alteration of the P53 pathway genes. All eight heme biosynthetic enzyme genes were expressed equivalently in cluster A cells from control and Flvcr1-deleted mice; however expression in Flvcr1-deleted cells was significantly reduced in clusters B-D. Of the 181 erythroid differentiation genes in the hallmark heme pathway, Gata1 had the greatest reduction (67%) in Flvcr1-deleted cells. Coupled two-way clustering analysis (CTWC) identified 150 genes co-regulated with Gata1 including 106 known GATA1 target genes which were all poorly upregulated in Flvcr1-deleted cells in clusters B-D. Independent microarray analysis of mRNA from control and Flvcr1-deleted CD71+ erythroid cells confirmed low Gata1 mRNA and low GATA1-dependent gene expression in the Flvcr1-deleted cells. To determine if excess heme was directly responsible for Gata1 downregulation, we treated K562, HEL-R, and primary human erythroid marrow cells with aminolevulinic acid (ALA) and iron to increase endogenous heme synthesis. In the primary cells, GATA1 protein decreased by 30-43% (p=0.03) within 15 minutes and 66% by 90 minutes (similar decreases observed in cell lines), suggesting that heme disrupts GATA1 protein function resulting in the loss of autoregulation and reduced GATA1 mRNA. Of 88 genes in the ribosome pathway, 73 were significantly upregulated in Flvcr1-deleted cells, including 16 of the 17 ribosomal protein genes linked to Diamond-Blackfan anemia (DBA) or del(5q) myelodysplastic syndrome (MDS). When heme synthesis was induced in primary human erythroid marrow cells with ALA and iron, the transcription of ribosome protein genes such as Rps19, Rps14, and Rpl35 increased, further supporting the concept that heme assures sufficient ribosome production for globin protein synthesis. While P53 activation is a key factor in ineffective erythropoiesis caused by ribosomal protein imbalance (i.e., DBA and del(5q) MDS), GSEA did not reveal any increased activation of the P53 pathway in Flvcr1-deleted cells. To confirm that P53 was not involved in the ineffective erythropoiesis caused by excess heme, we generated mice lacking both P53 and FLVCR1. These double mutant mice had severe macrocytic anemia (HGB 2.4±0.70 g/dL; MCV 56.5±4.3 fL) comparable to mice lacking just FLVCR1. Thus, GATA1 turns on heme synthesis and initiates the erythroid differentiation program. GATA1 with heme assure each cell's appropriate progression. Then heme turns off GATA1 to end differentiation. By linking excess heme to prematurely low GATA1, our data may also explain the ineffective (early termination of) erythropoiesis in DBA and reconcile the observations of Sci Transl Med 8:338ra67, 2016 and Nat Med 20:748, 2014. Disclosures No relevant conflicts of interest to declare.

scholarly journals HERF1, a Novel Hematopoiesis-Specific RING Finger Protein, Is Required for Terminal Differentiation of Erythroid Cells

1999 ◽  
Vol 19 (5) ◽  
pp. 3808-3815 ◽  
Author(s):  
Hironori Harada ◽  
Yuka Harada ◽  
Darin P. O’Brien ◽  
Dennis S. Rice ◽  
Clayton W. Naeve ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Ring Finger ◽  
Terminal Differentiation ◽  
Erythroid Differentiation ◽  
Erythroid Cells ◽  
Adult Mice ◽  
Finger Protein ◽  
Erythroleukemia Cell ◽  
Murine Erythroleukemia ◽  
Definitive Erythropoiesis

ABSTRACT The AML1/core binding factor β (CBFβ) transcription factor is essential for definitive hematopoiesis; however, the downstream pathways through which it functions remain incompletely defined. Using a differential cloning approach to define components of this pathway, we have identified a novel gene designated HERF1 (for hematopoietic RING finger 1), whose expression during development is dependent on the presence of functional AML1/CBFβ. HERF1 contains a tripartite RING finger–B box–α-helical coiled-coil domain and a C-terminal region homologous to the retproto-oncogene-encoded finger protein. Expression of HERF1during embryogenesis coincides with the appearance of definitive erythropoiesis and in adult mice is restricted to erythroid cells, increasing 30-fold during terminal differentiation. Importantly, inhibition of HERF1 expression blocked terminal erythroid differentiation of the murine erythroleukemia cell line MEL, whereas its overexpression induced erythroid maturation. These results suggest an important role for this protein in erythropoiesis.

scholarly journals Target of Erythropoietin, Fam210b, Regulates Erythroid Heme Synthesis By Control of Mitochondrial Iron Import and Regulation of Fech Activity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 849-849
Author(s):  
Yvette Y Yien ◽  
Jiahai Shi ◽  
Caiyong Chen ◽  
Jesmine Cheung ◽  
Anthony Grillo ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Fetal Liver ◽  
Iron Status ◽  
Cluster Formation ◽  
Adaptor Protein ◽  
Erythroid Differentiation ◽  
Erythroid Cells ◽  
Heme Synthesis ◽  
Iron Transporter ◽  
Mitochondrial Iron

Abstract Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well understood. To better understand these regulatory mechanisms, we profiled gene expression in EPO-treated fetal liver cells to identify novel iron regulatory genes (Figure A). We determined that FAM210B, a mitochondrial inner membrane protein, was essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation (Figure B). Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation (Figure C). These defects were corrected with a lipid-soluble small molecule iron transporter in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter, but is required for optimal mitochondrial iron import during erythroid differentiation (Figure D). FAM210B is also required for optimal FECH activity in differentiating erythroid cells. As FAM210B interacts with the terminal enzymes of the heme synthesis pathway, we propose that FAM210B functions as an adaptor protein to facilitate the formation of an oligomeric mitochondrial iron transport complex, which is required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis (Figure E). Collectively, our data reveal a novel mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism. Figure. Figure. Disclosures Palis: Rubies Therapeutics: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document