Iron transport proteins: Gateways of cellular and systemic iron homeostasis

Mitchell D Knutson

doi:10.1074/jbc.r117.786632

Abstract

Cellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease.

Highlights

The year 2017 marks the 20th anniversary of the groundbreaking discovery of DMT1, the first mammalian transmembrane iron transporter to be identified [1]
Systemic iron homeostasis–from intestinal iron uptake to iron utilization, recycling, and storage– can be largely understood by considering how iron is handled by four main cell types: enterocytes, erythrocyte precursors, macrophages, and hepatocytes
Greater than 95% of iron in plasma is bound to its circulating transport protein transferrin, which delivers most of its iron to erythrocyte precursors—i.e. erythroid progenitor cells of the bone marrow that differentiate into mature red blood cell (RBC)

Summary

Dietary iron absorption by the enterocyte

Human diets contain iron as heme or non-heme iron. Heme (iron-protoporphyrin IX) is found in meat, poultry, and seafood and derives mainly from hemoglobin and myoglobin. Dietary non-heme iron in the acidic microclimate at the absorptive surface of the proximal small intestine is transported across the apical membrane of enterocytes via DMT1 (SLC11A2, solute carrier family 11 member 2) (Fig. 2A) [1, 9]. Step is needed before iron transport by DMT1 This activity is generally thought to be mediated by the ferrireductase duodenal cytochrome B (DCYTB2; CYBRD1) located at the apical membrane of enterocytes [14]. Consistent with this possibility is the observation that Dcytb mRNA expression is markedly up-regulated in iron-deficient mouse intestines [14, 15]. Up-regulation of enterocyte ferritin resulting from ablation of intestinal iron regulatory proteins decreases iron absorption, even while DMT1 and ferroportin are markedly up-regulated [37]

Iron metabolism in erythrocyte precursors

Macrophage iron metabolism

Hepatocyte iron metabolism

Findings

Conclusions and future directions