Is erythroferrone finally the long sought-after systemic erythroid regulator of iron?

Abstract

Iron metabolism is regulated on the cellular and the systemic level. Over the last decade, the liver peptide "hepcidin" has emerged as the body's key irons store regulator. The long postulated "erythroid regulator of iron", however, remained elusive. Last year, evidence was provided, that a previously described myokine "myonectin" may also function as the long sought erythroid regulator of iron. Myonectin was therefore re-named "erythroferrone". This editorial provides a brief discussion on the two functions of erythroferrone and also briefly considers the emerging potential role of transferrin receptor 2 in erythropoiesis.

Keywords: Erythroid regulator of iron; Hepcidin; Iron metabolism; Myonectin; Systemic iron regulation.

Figure 1

Hepcidin in the regulation of systemic iron homeostasis. Systemic iron (Fe) homeostasis is primarily regulated by the hepcidin-ferroportin (FPN1) axis. Duodenal enterocytes import dietary Fe from several sources including heme Fe and non-heme Fe, which typically must be reduced at the level of the apical membrane by chemical reductants such as ascorbate[26,27] or by plasma membrane oxidoreductases (e.g., Dcytb), The reduced Fe then enters a common intracellular pool of Fe. “Sensing” the level of transferrin (TF) saturation and levels of Fe stores under conditions of Fe overload, hepatocytes up-regulate the expression of hepcidin, which is then released into the plasma where it can then bind to ferroportin (FPN1), thereby triggering FPN1 internalization and proteosomal degradation[1].

Figure 2

Two potential actions of erythroferrone. After blood loss, stress erythropoiesis is triggered by erythropoietin. This results in erythroferrone release from erythroblasts and in turn down-regulation of hepcidin. As a result, iron absorption and hemoglobin synthesis and erythropoiesis are increased (left). In response to feeding and exercise, myonectin (erythroferrone) produced by myotubes triggers fatty acid uptake by adipocytes and hepatocytes (right). Considering the function of erythroferrone in erythropoiesis, regulation of myoglobin is suggested to be a likely consequence of myonectin release (far right).