The Role of Mitochondrial Metabolism and Redox Signaling in Iron Deficiency Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2145-2145 ◽  
Author(s):  
Grant C Bullock ◽  
Chanté L Richardson ◽  
Valerie Schrott ◽  
Naomi D Gunawardena ◽  
Teague Nolan Cole ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Progenitor Cells ◽  
Mitochondrial Metabolism ◽  
Deficiency Anemia ◽  
Erythroid Progenitor ◽  
Iron Restriction ◽  
Cellular Iron ◽  
Clinical Observations ◽  
Erythroid Progenitor Cells ◽  
Mitochondrial Ros

Abstract Several clinical observations illustrate the link between iron and erythropoietin (EPO)-mediated signaling in committed erythroid progenitor cells. In iron deficiency anemia (IDA), erythropoiesis is blocked despite increased serum EPO concentrations. Intravenous iron improves the effectiveness of exogenous EPO in patients with EPO-refractory anemia of chronic disease. These clinical observations suggest that iron dominantly regulates EPO-receptor signaling. However, the mechanism of this iron-mediated signaling remains unclear. We recently demonstrated that 1) the aconitases, multifunctional iron-sulfur cluster proteins that convert citrate into isocitrate are essential in the iron- EPO-signaling pathway in erythroid progenitor cells, and that 2) isocitrate, the product of aconitase, can enhance the effectiveness of EPO during iron deficiency in vitro and in mice with IDA and in rats with the anemia of chronic inflammation. These observations suggest that isocitrate, or its derivatives that synergize with erythropoiesis stimulating agents, have important therapeutic application in the treatment of anemia. New data shows that cellular iron restriction regulates mitochondrial oxygen consumption rates (OCR) differentially over time during erythropoiesis, suggesting a novel link between mitochondrial function and erythropoeisis. It is unknown how iron deficiency induced inhibition of mitochondrial aconitase (ACO2) regulates mitochondrial metabolism during RBC production. Pilot data show that ACO2 inhibition by cellular iron deprivation or pharmacological inhibition of ACO2 decreases mitochondrial respiratory rates (RRs) and alters reactive oxygen species (ROS) production. Further, isocitrate normalizes mitochondrial RRs and ROS and restores RBC production. Importantly, disruption of mitochondrial ROS generation with a mitochondrial-specific anti-oxidant blocks RBC production and a subset of oxidant generators promote erythropoiesis. Targeted reduction of ACO2 protein expression and enzyme activity in iron replete stably transduced K562 cells decreases OCRs. This confirms the link between ACO2 and mitochondrial metabolism in human erythroid cells. These data inform our overarching hypothesis that iron-restriction inhibits ACO2, thereby inhibiting mitochondrial metabolism, resulting in the loss of a mitochondrial ROS signal that is required for erythropoiesis. The loss of this critical mitochondrial ROS signal inhibits the EPO signaling that is required for RBC production. These data also suggest that ACO2 is an iron-sensing regulator of mitochondrial metabolism and ROS signaling. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of Iron-Responsive Mitochondrial Metabolism and ROS in Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 216-216
Author(s):  
Chanté L Richardson ◽  
Valerie M Schrott ◽  
Claudette M St. Croix ◽  
Yinna Wang ◽  
Catherine G Corey ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Iron Deficiency ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Mitochondrial Metabolism ◽  
Superoxide Production ◽  
Deficiency Anemia ◽  
Erythroid Progenitor ◽  
Iron Restriction

Abstract Iron and erythropoietin (Epo) are intimately linked regulators of erythropoiesis. Moderate iron restriction suppresses erythropoiesis at the Epo-dependent, CFU-E stage, without induction of apoptosis and without suppression of other hematopoietic cell lineages. Iron modulates Epo bioactivity in patients with iron deficiency anemia (IDA) and patients with anemia of chronic disease and inflammation (ACDI). To conserve iron when supplies are low, this erythroid iron restriction response reduces iron consumption by suppressing erythropoiesis. The erythroid iron sensor is unknown. Aconitases are multifunctional iron-sulfur cluster proteins localized in the cytosol (Aco1) and mitochondria (Aco2) that convert citrate into isocitrate. We have shown that iron restriction inhibits Aco2 enzymatic activity leading to suppression of erythropoiesis in vitro, and these effects are reversed by isocitrate. Isocitrate corrects IDA in mice and ACDI in rats (Bullock GC, et al. Blood. 2010;116:97-108; Richardson CL, et al. J Clin Invest. 2013 Aug 1;123(8):3614-3623). Iron restriction also alters the cross-talk between transferrin receptor and Epo receptor signaling pathways. These results suggest that Aco2 is an iron-responsive regulator of erythropoiesis. We are investigating the downstream molecular signaling mechanisms by which iron restriction induced-inactivation of Aco2 suppresses erythropoiesis. Our novel preliminary data show that mitochondrial oxidative metabolism rates change over time during erythropoiesis and that iron restriction reduces erythroid mitochondrial metabolism 4 to 7-fold compared to iron replete controls. This iron restriction induced change in respiration is associated with a significant, 1.5 to 3-fold, increase in mitochondrial superoxide production without a corresponding increase in hydrogen peroxide. Importantly, these mitochondrial alterations are reproduced by direct inhibition of aconitase with fluoroacetate (FA) and are not due to changes in mitochondrial number. Further, isocitrate reverses the effects of iron restriction or aconitase inhibition on mitochondrial metabolism and attenuates superoxide production. Based on these data and the known role of reactive oxygen species (superoxide/hydrogen peroxide) in Epo signaling, we propose the overarching hypothesis that iron restriction inhibits mitochondrial aconitase which, in turn, alters erythroid mitochondrial metabolism and ROS signaling resulting in suppression of erythropoiesis (Figure 1). We show for the first time bioenergetics profiles from iron restricted and iron replete primary human erythroid progenitor cells undergoing erythropoiesis. We also show that moderate levels of iron restriction cause mitochondrial dysfunction and alterations in mitochondrial ROS in differentiating erythroid progenitors. The clinical relevance of this project lies in its potential for the development of new iron-free agonists and antagonists of red blood cell production. Agonists may benefit patients with anemia due to iron deficiency or chronic inflammation and antagonists may benefit patients with myeloproliferative neoplasms. Figure 1: Proposed mechanism of iron-dependent regulation of erythropoiesis Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Regulation of Cellular Iron Metabolism by Erythropoietin: Activation of Iron-Regulatory Protein and Upregulation of Transferrin Receptor Expression in Erythroid Cells

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 680-687 ◽  
Author(s):  
Günter Weiss ◽  
Tracey Houston ◽  
Stefan Kastner ◽  
Karin Jöhrer ◽  
Kurt Grünewald ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Regulatory Protein ◽  
Receptor Expression ◽  
General Mechanism ◽  
Iron Regulatory Protein ◽  
Erythroid Progenitor ◽  
Cellular Iron ◽  
Erythroid Progenitor Cells

Abstract Erythropoietin (Epo) is the central regulator of red blood cell production and acts primarily by inducing proliferation and differentiation of erythroid progenitor cells. Because a sufficient supply of iron is a prerequisite for erythroid proliferation and hemoglobin synthesis, we have investigated whether Epo can regulate cellular iron metabolism. We present here a novel biologic function of Epo, namely as a potential modulator of cellular iron homeostasis. We show that, in human (K562) and murine erythroleukemic cells (MEL), Epo enhances the binding affinity of iron-regulatory protein (IRP)-1, the central regulator of cellular iron metabolism, to specific RNA stem-loop structures, known as iron-responsive elements (IREs). Activation of IRP-1 by Epo is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and MEL, enhanced cell surface expression of trf-recs, and increased uptake of iron into cells. These findings are in agreement with the well-established mechanism whereby high-affinity binding of IRPs to IREs stabilizes trf-rec mRNA by protecting it from degradation by a specific RNase. The effects of Epo on IRE-binding of IRPs were not observed in human myelomonocytic cells (THP-1), which indicates that this response to Epo is not a general mechanism observed in all cells but is likely to be erythroid-specific. Our results provide evidence for a direct functional connection between Epo biology and iron metabolism by which Epo increases iron uptake into erythroid progenitor cells via posttranscriptional induction of trf-rec expression. Our data suggest that sequential administration of Epo and iron might improve the response to Epo therapy in some anemias.

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells

scholarly journals Fetal erythropoiesis in steel mutant mice. III. Defect in differentiation from BFU-E to CFU-E during early development

Blood ◽  
1978 ◽  
Vol 51 (3) ◽  
pp. 539-547 ◽  
Author(s):  
DH Chui ◽  
SK Liao ◽  
K Walker
Keyword(s):  
Progenitor Cells ◽  
Early Development ◽  
The Other ◽  
Mutant Mice ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Other Hand ◽  
Colony Forming Units ◽  
Fetal Erythropoiesis

Abstract Erythroid progenitor cells in +/+ and Sl/Sld fetal livers manifested as burst-forming units-erythroid (BFU-E) and colony-forming units- erythroid (CFU-E) were assayed in vitro during early development. The proportion of BFU-E was higher as mutant than in normal fetal livers. On the other hand, the proportion of CFU-E was less in the mutant than in the normal. These results suggest that the defect in Sl/Sld fetal hepatic erythropoiesis is expressed at the steps of differentiation that effect the transition from BFU-E to CFU-E.

scholarly journals The Raf‐1 Protein Mediates Insulin‐Like Growth Factor‐Induced Proliferation of Erythroid Progenitor Cells

Stem Cells ◽  
1998 ◽  
Vol 16 (3) ◽  
pp. 200-207 ◽  
Author(s):  
Marilyn R. Sanders ◽  
Hsienwie Lu ◽  
Frederick Walker ◽  
Sandra Sorba ◽  
Nicholas Dainiak
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

scholarly journals Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 870
Author(s):  
Tomasz M. Grzywa ◽  
Magdalena Justyniarska ◽  
Dominika Nowis ◽  
Jakub Golab
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Progenitor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Interleukin 10 ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

scholarly journals Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

1995 ◽  
Vol 15 (6) ◽  
pp. 3147-3153 ◽  
Author(s):  
G A Blobel ◽  
C A Sieff ◽  
S H Orkin
Keyword(s):  
Bone Marrow ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Erythroid Cell ◽  
High Dose ◽  
Dependent Manner ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.

scholarly journals DOT1L methyltransferase regulates the calcium influx in erythroid progenitor cells in response to erythropoietin

2020 ◽  
Author(s):  
Yi Feng ◽  
Shaon Borosha ◽  
Anamika Ratri ◽  
Sami M. Housami ◽  
V. Praveen Chakravarthi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Proximal Region ◽  
Yolk Sac ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

ABSTRACTErythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of hematopoietic progenitor cells. An important downstream response of EPO signaling is calcium influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca2+influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca2+influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in c-KIT positive erythroid progenitor cells is regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development, including early erythropoiesis. We previously reported that Dot1L knockout (Dot1L-KO) hematopoietic progenitors in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we have detected a marked downregulation of Trpc6 gene expression in Dot1L-KO progenitor cells in the yolk sac compared to wildtype. However, the expression of Trpc2, the positive regulator of Ca2+influx, remained unchanged. The promoter and the proximal region of the Trpc6 gene loci exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. As the loss of DOT1L affects the expression of TRPC6, which inhibits Ca2+influx by TRPC2, Dot1L-KO progenitor cells in the yolk sac exhibit accelerated and sustained high levels of Ca2+influx. Such heightened Ca2+ levels might have detrimental effects on the development of hematopoietic progenitor cells in response to erythropoietin.

Sign in / Sign up

Export Citation Format

Share Document