Iron metabolism in the central nervous system

Abstract

There are four cell types that have specific functions in iron metabolism; duodenal enterocytes, hepatocytes, erythroid cells, and reticuloendothelial macrophages. In these cells, iron absorption, storage, and export are critically regulated by several iron-metabolism proteins, including hepcidin. Iron is abundant in the brain, and iron homeostasis in the brain is relatively independent from that in other tissues because of the presence of the bloodbrain barrier. Iron uptake and transport in the brain depends on interactions between the vascular endothelial cells and perivascular astrocytes. Transferrin-bound iron (Tf-Fe3+) binds to the transferrin receptor 1 (TR1) on the luminal membrane of the endothelial cells, and then Tf-Fe3+-TR1 complex is internalized in the endosomes. In the acidic environment of the endosomes, iron is liberated from Tf. The mechanism by which free iron in the endosomes is exported into the interstitial space is still controversial. GPI-anchored ceruloplasmin on the end-foot processes of astrocytes oxidizes newly released Fe2+ to Fe3+, which binds to Tf in brain interstitial fluid, and then Tf-Fe3+ is taken up by neurons. Iron misregulation and abnormal iron accumulation are involved in several genetic and non-genetic neurological diseases through enhanced oxidative stress. Chelation therapy could be an effective disease-modifying approach for these conditions.