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.

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.

The Role of the Distal Erythropoietin Receptor in Iron Deficiency Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1312-1312
Author(s):  
Grant C. Bullock ◽  
Lorrie L. Delehanty ◽  
Anne-Laure A Talbot ◽  
Chante Richardson ◽  
Adam Goldfarb
Keyword(s):  
Iron Deficiency ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Signaling Pathways ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Deficiency Anemia ◽  
Red Cell ◽  
Iron Restriction

Abstract Abstract 1312 Anemia affects the quality of life and the life expectancy of millions of people in the U.S. Many patients are either intolerant or unresponsive to available treatments, so alternative strategies are needed. Red blood cell production requires the action of erythropoietin (Epo) on red blood cell precursors in the bone marrow. Iron restriction results in loss of Epo-responsiveness and anemia, despite increased serum Epo levels. Iron infusion restores Epo-responsiveness suggesting that iron dominantly regulates Epo-receptor (EpoR) signaling. Understanding how iron restriction regulates EpoR signaling pathways has major clinical significance. Agonists could offer an iron-free approach that enhances the response to Epo in anemia due to iron deficiency or chronic diseases. In addition, antagonists could be used to treat polycythemia vera or other myeloproliferative disorders. We have discovered that the aconitases, multifunctional iron-sulfur cluster proteins that convert citrate into isocitrate are key in connecting iron to Epo-signaling in early erythroid progenitors (GC Bullock, et. al. Blood 2010;116:97). We also discovered that isocitrate, the downstream product of aconitase, can enhance the effectiveness of Epo during iron deficiency in vitro and in vivo in mice with IDA. These observations suggest that isocitrate or derivatives of isocitrate that synergize with erythropoiesis stimulating agents (ESAs) have important therapeutic application in the treatment of anemia. Deletion of EpoR in mice is incompatible with life, however mice and humans that express truncated EpoR show increased production of red blood cells. These observations suggest that the distal cytoplasmic domain of the EpoR inhibits production of red cells and may play a critical role in iron deficiency anemia. EpoR mutant mice lacking the distal half of the cytoplasmic domain of the EpoR (EpoR-H mice) and mice with the same EpoR truncation mutation plus an additional mutation of tyrosine 343 (EpoR-HM mice) show near normal levels of steady state erythropoiesis. To determine the role of the distal domain in erythroid suppression during iron deficiency, EpoR-H, EpoR-HM and EpoR-wildtype mice were fed a low iron diet and compared by weekly CBCs and flow cytometry. EpoR-H mutant mice continue to efficiently produce red blood cells during iron deficiency. And this occurs despite a decrease in hemoglobin. EpoR-HM mice produce fewer rbcs than EpoR-H mice, however rbc production by EpoR-HM mice resists the suppressive effects of iron restriction. Similar experiments also suggest that the distal EpoR is necessary for the isocitrate-mediated enhancement of Epo-driven erythropoiesis. In addition to aconitase/isocitrate and the distal EpoR other candidate key signaling components of this Epo-dependent, iron-responsive pathway have been identified in our recent preliminary experiments. These components include specific protein kinase C (PKC) isozymes, AKT1 and ERK1/2. These findings support a new model of iron sensing by aconitase/isocitrate that alters EpoR signaling to decrease red blood cell production and conserve iron when supplies are low. This model fits better than older “heme-deficiency” models because disorders in heme synthesis block red cell differentiation at a later stage. This model also has potential to explain changes seen in other tissues during chronic iron deficiency. Nutritional iron restriction may have unmasked a new role for the distal EpoR in red cell development and implicated new iron-responsive Epo signaling pathways that can be used to develop new therapeutic agonists and antagonists of Epo. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of iron repletion in adult iron deficiency anemia and other diseases

2019 ◽  
Vol 104 (3) ◽  
pp. 153-161 ◽  
Author(s):  
Benjamin Elstrott ◽  
Lubna Khan ◽  
Sven Olson ◽  
Vikram Raghunathan ◽  
Thomas DeLoughery ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Deficiency Anemia

Role of Iron Supplementation in Reducing Severity of Depression: A Review

2020 ◽  
pp. 67-76
Author(s):  
OJS Admin
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Supplementation ◽  
Reproductive Age ◽  
Deficiency Anemia ◽  
Essential Nutrient ◽  
Severity Of Depression ◽  
The Impact ◽  
Clinical Problems

Depression is a public health disorder, ranking third after respiratory and cardiac diseases. There were many evidences that iron deficiency anemia (IDA) is one of the foremost causes regarding nutritional pointof view for depression. We reviewed these evidences that IDAlinking to depression. We identified seventeen studies in four databases including randomized-controlled trials (RCTs) and observational studies assessing the impact of IDAand iron supplementation on the risk of depression. We extracted data on the basis of sample size, geographical region, measures of depression, hemoglobin, iron levels and intake of iron supplementation and critically appraised the results from the studies. Eleven out of sixty one studies were experimental, which indicated that dietary supplementation particularly iron supplementation had an association (r − 0.19 to −0.43 and ORs 1.70–4.64) with severity of depression. Evidences showed that women of reproductive age were more vulnerable to iron deficiency anemia than other population. Low ferritin and low hemoglobin level were associated with severity of depression. Iron is an essential nutrient for all living creatures, as a cofactor of various enzymes and plays significant role in environmental stimulant for the articulation of numerous virulence factors. Many clinical problems are caused by iron deficiency. Therefore, this review intended to highlight the important role of iron supplementation in reducing the severity of depression.

The Importance of Iron To Support Optimum Cognitive Development

2021 ◽  
Vol 5 (1-1) ◽  
pp. 25-32
Author(s):  
Rini Sekartini
Keyword(s):  
Iron Deficiency ◽  
Iron Supplementation ◽  
Fetal Brain ◽  
Nutrient Deficiency ◽  
Deficiency Anemia ◽  
Neural Systems ◽  
Brain Anatomy ◽  
Micronutrient Status ◽  
The Central Nervous System

The fetal brain anatomy development starts during the last trimester of pregnancy and continue in early months of life. This critical process makes it vulnerable to insufficient nutrition, while brain growth continues into adulthood, micronutrient status can affect functioning beyond childhood. Iron is an important nutrient for the production and growth of cells in the immune and neural systems. Iron deficiency (ID) is the most common nutrient deficiency in the world, affecting about half of all pregnant women and their offspring. Iron deficiency anemia has long been believed to have an effect on the central nervous system. Iron deficiency in late trimester and in newborn leads to abnormal cognitive function and emotional control that may continue in adulthood. In summary, despite some evidence that iron supplementation enhances cognitive performance. Evidence of the role of iron in brain development and the effect of iron deficiency or iron supplementation on early development is uncertain.

scholarly journals Iron, Ferritin and Hepcidin Levels in Patients with Iron Deficiency Anemia

2021 ◽  
Vol 8 (5) ◽  
pp. 137-139
Author(s):  
Rabaa Khaled Abdel Salam ◽  
Saria Naji Mohsin
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Transport ◽  
Blood Parameters ◽  
Deficiency Anemia ◽  
Control Group ◽  
Blood Picture ◽  
Cellular Kinetics ◽  
And Storage

This study was conducted to identify the role of some blood parameters, levels of some hormones, proteins, and cellular kinetics that have a role in iron transport and storage, in addition to their relationship with each other and with blood and sex parameters for patients with severe and moderate iron deficiency anemia, and to compare the parameters with healthy people. The study period lasted for the period from (December 2020 until March 2021) The presence of iron deficiency anemia was confirmed by examining the blood picture and the criteria of hepcidin and ferritin. The results showed a significant decrease in the in the concentration of hepcidin, ferritin and iron in patients compared to the control group.

scholarly journals Maternal Hepcidin Suppression Is Essential for Healthy Pregnancy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Veena Sangkhae ◽  
Tomas Ganz ◽  
Elizabeta Nemeth
Keyword(s):  
Iron Deficiency ◽  
Molecular Mechanisms ◽  
Hematological Parameters ◽  
Critical Role ◽  
Physiological Mechanism ◽  
Deficiency Anemia ◽  
Private Company ◽  
Iron Stores ◽  
Primary Mouse

Iron is essential for maternal and fetal health during pregnancy, and iron requirements increase substantially in the second half of gestation1. However, the molecular mechanisms ensuring increased iron availability during pregnancy are not well understood. Hepcidin is the key iron-regulatory hormone and functions by occluding and degrading the iron exporter ferroportin (FPN) to inhibit dietary iron absorption and mobilization of iron from stores. In healthy human and rodent pregnancies, maternal hepcidin decreases starting in the second trimester and is nearly undetectable by late pregnancy2,3 (Figure A). We explored the role of maternal and embryo hepcidin in regulating embryo iron endowment using mouse models. By generating combinations of dams and embryos lacking hepcidin or not, we showed that in normal mouse pregnancy, only maternal but not embryo or placental hepcidin determines embryo iron endowment4. Maternal hepcidin was inversely related to embryo iron stores, and embryos from hepcidin-deficient dams had significantly higher hepatic iron stores regardless of their own hepcidin genotype. When maternal hepcidin was elevated during the second half of pregnancy in mice by administering a hepcidin mimetic, this led to dose-dependent embryo iron deficiency, anemia, and in severe cases, embryo death4. Embryos were particularly sensitive to maternal iron restriction as they developed iron deficiency in the liver and the brain even when maternal hematological parameters were unaffected. These data highlight the critical role of maternal hepcidin suppression for heathy pregnancy. Yet, the physiological mechanism of maternal hepcidin suppression remains unknown. We showed in mice that maternal hepcidin decreases prior to a significant decrease in liver iron and without any changes in serum iron, suggesting that maternal hepcidin suppression is not driven solely by iron deficiency. Using an in vitro model, we determined that the placenta secretes a hepcidin-suppressing factor. Exposure of primary mouse hepatocytes to supernatants from cultured human placenta cells, but not control media, suppressed hepcidin mRNA more than 10-fold (Figure B) and for up to 48hrs. The suppressive factor in the supernatant was >100kDa in size and not associated with exosomes. Studies to identify the placenta-derived hepcidin suppressor are ongoing. In summary, suppression of maternal hepcidin is essential to ensure adequate iron supply for transfer to the fetus and for the increase in maternal red blood cell mass2, and a placenta-derived hepcidin suppressor likely plays an important role in this adaptation. 1Fisher AL and Nemeth E, Am J Clin Nutr, 2017 2Sangkhae V et al, JCI, 2020 3van Santen S et al, Clin Chem Lab Med, 2013 4Sangkhae V et al, Blood, 2020 Figure 1 Disclosures Ganz: Global Blood Therapeutics: Consultancy; Ionis Pharmaceuticals: Consultancy; American Regent: Consultancy; Rockwell: Consultancy; Vifor: Consultancy; Astellas: Consultancy; Akebia: Consultancy; Gossamer Bio: Consultancy; Silarus Therapeutics: Current equity holder in private company; Sierra Oncology: Consultancy; Ambys: Consultancy; Disc Medicine: Consultancy; Intrinsic LifeSciences: Current equity holder in private company. Nemeth:Intrinsic LifeSciences: Current equity holder in private company; Silarus Therapeutics: Current equity holder in private company; Ionis Pharmaceuticals: Consultancy; Protagonist: Consultancy; Vifor: Consultancy.

THEORETICAL ASPECTS OF TREATMENT OF IRON DEFICIENCY ANEMIA IN CHILDREN (review)

2021 ◽  
pp. 32-39
Author(s):  
Н.А. САДИЕВА ◽  
А.Э. МАМЕДОВА
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
The Body ◽  
Deficiency Anemia ◽  
Treatment Protocols

В публикации авторы представили теоретический обзор распространения анемии у детей во всем мире, в том числе и в Азербайджане, роли железа в организме, причинах возникновения железодефицитной анемии и его классификации, особенностях проведения ферротерапии у детей, классификации железосодержащих средств применяемых в Азербайджане, протоколах лечения ЖДА у детей во всем мире, в том числе и в Азербайджане. In the publication the authors presented a theoretical review of the spread of anemia in children worldwide, including Azerbaijan, the role of iron in the body, the causes of iron deficiency anemia and its classification, the peculiarities of ferrotherapy in children, the classification of iron-containing agents used in Azerbaijan, the treatment protocols for iron deficiency in children worldwide, including in Azerbaijan.

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