New insights into iron regulation and erythropoiesis

Abstract

Purpose of review Iron homeostasis and erythropoiesis regulate each other to ensure optimal delivery of oxygen and iron to cells and tissues. Defining the mechanisms of this crosstalk is important for understanding the pathogenesis of common conditions associated with disordered iron metabolism and erythropoiesis. Recent findings Stress erythropoiesis causes suppression of hepcidin to increase iron availability for hemoglobin synthesis. The erythroid hormone erythroferrone (ERFE) was identified as the mediator of this process. ERFE and additional candidates (TWSG1 and GDF15) may also mediate hepcidin suppression in ineffective erythropoiesis. Several mechanisms by which iron regulates erythropoiesis were also recently identified. Iron deficiency suppresses erythropoietin production via the IRP1–HIF2α axis to prevent excessive iron usage by erythropoiesis during systemic iron restriction. Iron restriction also directly impairs erythroid maturation by inhibiting aconitase, and this can be reversed by the administration of the aconitase product isocitrate. Another novel target is GDF11, which is thought to autoinhibit erythroid maturation. GDF11 traps show promising pharmacologic activity in models of both ineffective erythropoiesis and iron-restricted anemia. Summary This review summarizes exciting advances in understanding the mechanisms of iron and erythropoietic regulation, and development of novel therapeutic tools for disorders resulting from dysregulation of iron metabolism or erythropoiesis.

EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia

“…Under pathological conditions (e.g. hemorrhage or hemolysis), erythroid precursors request a delivery of sufficient iron in bone marrow for the production of erythrocytes [2,3]. The liver-produced hormone hepcidin is identified as the main circulating regulator of systemic iron balance, and its suppression in anemia might result from hypoxia or EPO [6][7][8].…”

“…Hemolytic anemia could induce stress erythropoiesis in bone marrow and a remarkable alteration of iron homeostasis in order to meet the elevated demand of iron supply for hemoglobin synthesis and erythroid cell maturation [2,3]. Erythropoiesis and iron homeostasis have been proved to regulate each other to ensure an optimal amount of oxygen and iron supply to cells and tissues [4,5].…”

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

“…There is elevated formation of free radicals and increased oxidative stress in erythroid precursors due to enhanced demand of iron for hemoglobin synthesis and accumulated hemoglobin content [20,66,67], and erythroid precursors may be also subjected to oxidative stress from foreign chemicals including drugs for medicinal purposes and environmental toxicants [19,22,68]. Therefore, erythroid cells are highly sensitive to oxidative stress, and aberrant ROS accumulation incurs impaired erythropoiesis, shortened lifespan of RBCs and even hemolysis [66,69,70].…”

“…However, whether Nrf2 also conducts cytoprotection through miRNA-dependent mechanisms is still largely unknown thus far. During the maturation of proerythroblasts into red blood cells (RBCs), erythroid precursors experience various stresses from both inside and outside [19][20][21][22]. The increased demand of iron for hemoglobin synthesis in erythroblast results in enhanced formation of labile iron and consequently generation of free radicals, oxidative stress and cytotoxicity [19][20][21].…”

“…During the maturation of proerythroblasts into red blood cells (RBCs), erythroid precursors experience various stresses from both inside and outside [19][20][21][22]. The increased demand of iron for hemoglobin synthesis in erythroblast results in enhanced formation of labile iron and consequently generation of free radicals, oxidative stress and cytotoxicity [19][20][21]. In addition, erythroid precursors may be also subjected to diverse stresses in bone marrow, such as hypoxia, mechanical stress, radiation, foreign chemicals and environmental toxicants [23][24][25][26].…”