Ironing out mechanisms of iron homeostasis and disorders of iron deficiency
Navid Koleini, Jason S. Shapiro, Justin Geier, Hossein Ardehali
Navid Koleini, Jason S. Shapiro, Justin Geier, Hossein Ardehali
View: Text | PDF
Review

Ironing out mechanisms of iron homeostasis and disorders of iron deficiency

Abstract

Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients’ symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.

Authors

Navid Koleini, Jason S. Shapiro, Justin Geier, Hossein Ardehali

×

Figure 2

Depiction of the mechanism of ACD and cellular and mitochondrial iron regulation.

Options: View larger image (or click on image) Download as PowerPoint
Depiction of the mechanism of ACD and cellular and mitochondrial iron re...
(A) Graphic of pathways leading to functional iron deficiency (ID). Inflammation increases hepcidin expression, inhibiting intestinal and macrophage iron release into the circulation. This simultaneously decreases systemic iron bioavailability and traps iron within tissues, leading to functional ID despite normal iron storage. (B) (i) Iron bound to TF is absorbed by hepatocytes via binding to TFR1 and subsequent receptor-mediated endocytosis. Iron is reduced from Fe3+ to Fe2+ and released from TFR1-TF in acidified endolysosomes by the action of the STEAP family of ferrireductases. Fe2+ is then exported to the cytosol via DMT1, while TFR1 and TF are recycled back to the cell surface. (ii) Within the cytosol, iron is stored by binding to FTN to reduce free-iron toxicity. Iron is released from FTN via receptor (NCOA4)-mediated autophagy and is exported to the cytosol via lysosomal DMT1. (C) Elemental iron is imported across the mitochondrial membrane by MFRN1/2. Synthesis of Fe-S clusters and heme occurs primarily within mitochondria. Fe-S clusters are exported into the cytosol via unknown mechanisms, but may require ABCB7 and ABCB8.