Ironing out mechanisms of iron homeostasis and disorders of iron deficiency
Navid Koleini, … , Justin Geier, Hossein Ardehali
Navid Koleini, … , Justin Geier, Hossein Ardehali
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e148671. https://doi.org/10.1172/JCI148671.
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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

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Figure 1

Depiction of the mechanism of systemic iron regulation.

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Depiction of the mechanism of systemic iron regulation. (i) Heme-bound i...
(i) Heme-bound iron is absorbed into duodenal enterocytes, possibly via HCP1. Enterocyte HO-1 releases iron from heme’s porphyrin ring, producing Fe2+, biliverdin, and carbon monoxide. Fe2+ iron is then exported into the circulation by FPN1. (ii) Absorbed Fe3+ is reduced to Fe2+ at the brush border by low pH and ferrireductases, enabling its transport by DMT1 into duodenal enterocytes. Fe2+ is either bound to FTN within the enterocyte, limiting the intracellular pool of free iron, or released into the circulation by FPN1, where it is oxidized to Fe3+ by hephaestin (HPE) and ceruloplasmin (CP) and bound to TF for transport. (iii) Macrophages identify senescent RBCs no longer expressing CD47 via SIRPα and recycle RBC iron through phagocytosis. Upon fusion of phagosomes with lysosomes, heme is released from hemoglobin and transported to the cytosol via HRG1. In the cytosol, heme-bound iron is extracted by HO-1 and exported by FPN1. Fe2+ is then oxidized to Fe3+ by CP and binds to TF for transport. (iv) When systemic iron levels are sufficiently replete, hepcidin is produced by the liver, binds to FPN1 on macrophages and enterocytes, and promotes its degradation. This prevents intestinal and macrophage iron release into the circulation. Binding of BMP6 to BMP receptor and its coreceptor HJV activates SMAD signaling and promotes transcription of hepcidin.