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.

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.

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 Transferrin: physiologic behavior and clinical implications

Blood ◽  
1984 ◽  
Vol 64 (4) ◽  
pp. 763-767 ◽  
Author(s):  
HA Huebers ◽  
CA Finch
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Regulatory Mechanism ◽  
Effective Means ◽  
Molecular Defect ◽  
Life Saving ◽  
Receptor Number ◽  
Idiopathic Hemochromatosis ◽  
Definition Of ◽  
Diferric Transferrin

Abstract The transferrin iron transport system, along with its procurement sites and delivery receptors, provides a highly effective means of satisfying internal iron requirements. Iron uptake by individual tissues is determined by their receptor number, by the relative amounts of monoferric and diferric transferrin in circulation, and by the amount of available iron in donor tissues. Although the modus operandi of this system under basal conditions has been characterized, its exquisite regulation remains an enigma. In some manner, the procurement of iron is determined by iron requirements. What seems to be an inappropriate behavior of the absorptive mechanism in thalassemia and certain other erythroid overload states may actually be life-saving in the absence of transfusion, since it results in higher levels of plasma iron and thereby higher levels of erythropoiesis. The definition of the regulatory mechanism in such conditions may well lead to an understanding of the molecular defect in idiopathic hemochromatosis.

scholarly journals Iron uptake by human reticulocytes at physiologic and sub-physiologic concentrations of iron transferrin: the effect of interaction with aluminum transferrin [see comments]

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2347-2353 ◽  
Author(s):  
M Cochran ◽  
V Chawtur ◽  
ME Jones ◽  
EA Marshall
Keyword(s):  
Iron Uptake ◽  
Surface Phenomena ◽  
Conventional View ◽  
Parallel Processes ◽  
Placental Blood ◽  
Diferric Transferrin ◽  
Transferrin Uptake ◽  
Kinetics Of ◽  
Insight Into

Abstract We have studied the interaction, in vitro, between diferric transferrin (FeTr), aluminum transferrin (AlTr), and human reticulocytes harvested from human placental blood. In particular, we aimed to determine the extent to which the kinetics of AlTr and FeTr differed. Using transferrin labeled with either 59Fe or 125I, the association of radiotracer with reticulocytes, as a function both of time and of transferrin concentration, was examined. Under the conditions of the experiments, the data are consistent with a mechanism involving at least three processes. Two early processes acting in parallel behave as a high-affinity saturable receptor and a low-affinity non-saturable receptor, neither of which distinguish between AlTr and FeTr. In a subsequent process, AlTr and FeTr exhibit different kinetics. This third process may be saturated by FeTr but not by AlTr. Interpreted in terms of a current conventional view of metallo-transferrin uptake, we conjecture that the early parallel processes involve cell surface phenomena including classical transferrin-receptor binding, and that the subsequent process represents events, possibly intracellular, involved in metallo-transferrin dissociation or further iron transport. The extent to which AlTr influences the interaction of FeTr with reticulocytes offers insight into both the normal physiology of iron uptake and the potential for toxicity by aluminum.

scholarly journals Iron uptake by human reticulocytes at physiologic and sub-physiologic concentrations of iron transferrin: the effect of interaction with aluminum transferrin [see comments]

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2347-2353
Author(s):  
M Cochran ◽  
V Chawtur ◽  
ME Jones ◽  
EA Marshall
Keyword(s):  
Iron Uptake ◽  
Surface Phenomena ◽  
Conventional View ◽  
Parallel Processes ◽  
Placental Blood ◽  
Diferric Transferrin ◽  
Transferrin Uptake ◽  
Kinetics Of ◽  
Insight Into

We have studied the interaction, in vitro, between diferric transferrin (FeTr), aluminum transferrin (AlTr), and human reticulocytes harvested from human placental blood. In particular, we aimed to determine the extent to which the kinetics of AlTr and FeTr differed. Using transferrin labeled with either 59Fe or 125I, the association of radiotracer with reticulocytes, as a function both of time and of transferrin concentration, was examined. Under the conditions of the experiments, the data are consistent with a mechanism involving at least three processes. Two early processes acting in parallel behave as a high-affinity saturable receptor and a low-affinity non-saturable receptor, neither of which distinguish between AlTr and FeTr. In a subsequent process, AlTr and FeTr exhibit different kinetics. This third process may be saturated by FeTr but not by AlTr. Interpreted in terms of a current conventional view of metallo-transferrin uptake, we conjecture that the early parallel processes involve cell surface phenomena including classical transferrin-receptor binding, and that the subsequent process represents events, possibly intracellular, involved in metallo-transferrin dissociation or further iron transport. The extent to which AlTr influences the interaction of FeTr with reticulocytes offers insight into both the normal physiology of iron uptake and the potential for toxicity by aluminum.

scholarly journals Transferrin: physiologic behavior and clinical implications

Blood ◽  
1984 ◽  
Vol 64 (4) ◽  
pp. 763-767 ◽  
Author(s):  
HA Huebers ◽  
CA Finch
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Regulatory Mechanism ◽  
Effective Means ◽  
Molecular Defect ◽  
Life Saving ◽  
Receptor Number ◽  
Idiopathic Hemochromatosis ◽  
Definition Of ◽  
Diferric Transferrin

The transferrin iron transport system, along with its procurement sites and delivery receptors, provides a highly effective means of satisfying internal iron requirements. Iron uptake by individual tissues is determined by their receptor number, by the relative amounts of monoferric and diferric transferrin in circulation, and by the amount of available iron in donor tissues. Although the modus operandi of this system under basal conditions has been characterized, its exquisite regulation remains an enigma. In some manner, the procurement of iron is determined by iron requirements. What seems to be an inappropriate behavior of the absorptive mechanism in thalassemia and certain other erythroid overload states may actually be life-saving in the absence of transfusion, since it results in higher levels of plasma iron and thereby higher levels of erythropoiesis. The definition of the regulatory mechanism in such conditions may well lead to an understanding of the molecular defect in idiopathic hemochromatosis.

Nitrogen Monoxide Inhibits Heme Synthesis In Reticulocytes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4252-4252
Author(s):  
Marc Mikhael ◽  
Sameer Apte ◽  
Shan Soe-Lin ◽  
Prem Ponka
Keyword(s):  
Iron Metabolism ◽  
Iron Uptake ◽  
Aminolevulinic Acid ◽  
Conflicts Of Interest ◽  
No Production ◽  
Erythroid Cells ◽  
Anemia Of Chronic Disease ◽  
Heme Synthesis ◽  
Eif2α Phosphorylation ◽  
Globin Synthesis

Abstract Abstract 4252 Anemia of chronic disease (ACD) is a condition that often manifests in patients with chronic immune activation due to chronic infections, autoimmune disorders, cancer and other diseases. The pathogenesis of ACD is complex and involves inefficient erythropoietin production, immune-mediated inhibition of erythropoiesis, and retention of iron in hemoglobin-processing macrophages. During their development, erythroid cells are closely associated with macrophages. In inflammatory conditions, activated macrophages generate large quantities of the gaseous molecule, nitric oxide (NO), which has numerous effects on iron metabolism. In this study, we explored the possibility that NO affects iron metabolism in erythroid cells. We treated reticulocytes with the NO donors, sodium nitroprusside (SNP) and S-Nitroso-N-acetyl-D,L-penicillamine (SNAP). We show that NO inhibits 59Fe incorporation from 59Fe-transferrin into reticulocytes and their heme. Significantly, 5-aminolevulinic acid (ALA, the product of ALA synthase, which catalyzes the first step of heme synthesis) reversed the SNP-mediated decrease in 59Fe incorporation into heme but not the cellular 59Fe uptake. In addition, SNP treatment led to an increase in eIF2α phosphorylation (which is known to occur in heme-deficient cells) and decreased globin translation. Importantly, the addition of ALA to SNP-treated reticulocytes prevented the effect of SNP on eIF2α phosphorylation and reversed globin synthesis inhibition. This indicates that in SNP treated reticulocytes, the phosphorylation of eIF2α and inhibition of globin synthesis occur indirectly, via NO's effect on erythroid-specific ALA synthase (ALA-S2). These results led us to conclude that NO has two distinct effects on reticulocytes, namely: a decrease in ALA-S2 activity and a decrease in transferrin-mediated iron uptake. The profound impact of NO on heme synthesis, iron uptake and globin translation in reticulocytes raises the possibility that NO production by macrophages could also contribute to ACD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pancreatic β-cells express hepcidin, an iron-uptake regulatory peptide

2008 ◽  
Vol 197 (2) ◽  
pp. 241-249 ◽  
Author(s):  
Hasan Kulaksiz ◽  
Evelyn Fein ◽  
Peter Redecker ◽  
Wolfgang Stremmel ◽  
Guido Adler ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Secretory Granules ◽  
Rinm5f Cells ◽  
Β Cells ◽  
Additional Source ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Vital Functions ◽  
Immunohistochemical Studies ◽  
Insight Into

Body iron is involved in various vital functions. Its uptake in the intestine is regulated by hepcidin, a bioactive peptide originally identified in plasma and urine and subsequently in the liver. In the present study, we provide evidence at the transcriptional and translational levels that hepcidin is also expressed in the pancreas of rat and man. Immunohistochemical studies localized the peptide exclusively to β-cells of the islets of Langerhans. Immunoelectron microscopical analyses revealed that hepcidin is confined to the insulin-storing β-cell secretory granules. As demonstrated in insulinoma-derived RINm5F cells, the expression of hepcidin in β-cells is regulated by iron. Based on the present findings we conclude that pancreatic islets are an additional source of the peptide hepcidin. The localization of this peptide to β-cells suggests that pancreatic β-cells may be involved in iron metabolism in addition to their genuine function in blood glucose regulation. In view of the various linked iron/glucose disorders in the pancreas, the present findings may provide an insight into the phenomenology of intriguing mutual relationships between iron and glucose metabolisms.

scholarly journals Antibodies to the Iron Uptake ABC Transporter Lipoproteins PiaA and PiuA Promote Opsonophagocytosis of Streptococcus pneumoniae

2005 ◽  
Vol 73 (10) ◽  
pp. 6852-6859 ◽  
Author(s):  
Maha Jomaa ◽  
Jose Yuste ◽  
James C. Paton ◽  
Christopher Jones ◽  
Gordon Dougan ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Abc Transporters ◽  
Iron Uptake ◽  
Iron Transport ◽  
Antibody Responses ◽  
Igg Subclass ◽  
Specific Enzyme ◽  
Low Levels ◽  
Passive Vaccination ◽  
Neutrophil Cell

ABSTRACT PiaA and PiuA are the lipoprotein components of the Pia and Piu Streptococcus pneumoniae iron uptake ABC transporters and are required for full virulence in mouse models of infection. Active or passive vaccination with recombinant PiuA and PiaA protects mice against invasive S. pneumoniae disease. In this study we have analyzed the antibody responses and mechanism of protection induced by PiuA and PiaA in more detail. For both proteins, two booster vaccinations induced stronger antibody responses in mice than a single or no booster vaccinations, and 5 μg of protein induced similar levels of antibody responses as 20 μg. Immunoglobulin G (IgG) subclass-specific enzyme-linked immunosorbent assays demonstrated that the antibody response to PiuA and PiaA was predominantly IgG1, with induction of only low levels of IgG2a. Anti-PiaA and anti-PiuA polyclonal rabbit antibodies bound to the surface of live S. pneumoniae when assessed by flow cytometry but did not inhibit growth of S. pneumoniae in cation-depleted medium or bacterial susceptibility to the iron-dependent antibiotic streptonigrin. However, anti-PiaA and anti-PiuA did increase complement-independent and -dependent opsonophagocytosis of different serotypes of S. pneumoniae by the human neutrophil cell line HL60. Hence, vaccination with PiaA and PiuA protects against S. pneumoniae infection by inducing antibodies that promote bacterial opsonophagocytosis rather than inhibiting iron transport.

Sign in / Sign up

Export Citation Format

Share Document