The mutual control of iron and erythropoiesis

Abstract

Summary Background Iron is essential for hemoglobin synthesis during terminal erythropoiesis. To supply adequate iron the carrier transferrin is required together with transferrin receptor endosomal cycle and normal mitochondrial iron utilization. Iron and iron protein deficiencies result in different types of anemia. Iron‐deficiency anemia is the commonest anemia worldwide due to increased requirements, malnutrition, chronic blood losses and malabsorption. Mutations of transferrin, transferrin receptor cycle proteins, enzymes of the first step of heme synthesis and iron sulfur cluster biogenesis lead to rare anemias, usually accompanied by iron overload. Hepcidin plays an indirect role in erythropoiesis by controlling plasma iron. Inappropriately high hepcidin levels characterize the rare genetic iron‐refractory iron‐deficiency anemia (IRIDA) and the common anemia of chronic disease. Iron modulates both effective and ineffective erythropoiesis: iron restriction reduces heme and alpha‐globin synthesis that may be of benefit in thalassemia. Material and Methods This review relies on the analysis of the most recent literature and personal data. Results Erythropoiesis controls iron homeostasis, by releasing erythroferrone that inhibits hepcidin transcription to increase iron acquisition in iron deficiency, hypoxia and EPO treatment. Erythroferrone, produced by EPO‐stimulated erythropoiesis, inhibits hepcidin only when the activity of BMP/SMAD pathway is low, suggesting that EPO somehow modulates the latter signaling. Erythroblasts sense circulating iron through the second transferrin receptor (TFR2) that, in animal models, modulates the sensitivity of the erythroid cells to EPO. Discussion The advanced knowledge of the regulation of systemic iron homeostasis and erythropoiesis‐mediated hepcidin regulation is leading to the development of targeted therapies for anemias and iron disorders.

Ferritinophagy/ferroptosis: Iron‐related newcomers in human diseases

“…Mature red cells are rich in hemoglobin, which shows strong iron dependence. Iron is essential for sulfur cluster synthesis and mostly presents as heme in the hemoglobin of maturing erythrocytes (Camaschella, Pagani, Nai, & Silvestri, 2016). Due to the significance of ferritinophagy in regulating cellular iron availability, NCOA4-mediated ferritinophagy is required for the survival process of erythropoiesis (Mancias et al, 2015).…”

Erythroferrone and iron status parameters levels in pediatric patients with iron deficiency anemia

“…In IDA, the master negative iron regulator hepcidin is suppressed to allow the compensatory mechanism of increased iron absorption from the intestine and reduced iron sequestration in macrophages …”

“…7 In IDA, the master negative iron regulator hepcidin is suppressed to allow the compensatory mechanism of increased iron absorption from the intestine and reduced iron sequestration in macrophages. 8 Estimation of serum level of erythroferrone and its correlation with iron status parameters have not yet been analyzed in cases with iron deficiency anemia. So, the aim of this study was to highlight on serum erythroferrone and iron status parameters levels in pediatric patient with iron deficiency anemia.…”

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

“…However, increased hepcidin synthesis decreases the iron stock that must be available to the erythroblasts for erythropoiesis to occur. Iron is transported in the circulation bound to transferrin and released to erythroblasts by the interaction between holo-Tf and its TFR1 and TFR2 receptors present in erythroid precursors [45]. …”