Physiology of iron transport and the hemochromatosis gene

Abstract

Iron is essential for fundamental cell functions but is also a catalyst for chemical reactions involving free radical formation, potentially leading to oxidative stress and cell damage. Cellular iron levels are therefore carefully regulated to maintain an adequate substrate while also minimizing the pool of potentially toxic "free iron." The main control of body iron homeostasis in higher organisms is placed in the duodenum, where dietary iron is absorbed, whereas no controlled means of eliminating unwanted iron have evolved in mammals. Hereditary hemochromatosis, the prototype of deregulated iron homeostasis in humans, is due to inappropriately increased iron absorption and is commonly associated to a mutated HFE gene. The HFE protein is homologous to major histocompatibility complex class I proteins but is not an iron carrier, whereas biochemical and cell biological studies have shown that the transferrin receptor, the main protein devoted to cellular uptake of transferrin iron, interacts with HFE. This review focuses on recent advances in iron research and presents a model of HFE function in iron metabolism.

Mechanisms of iron loading and toxicity

“…Each day 1-2 mg of iron from dietary sources is absorbed by the proximal small intestine, with the precise amount reflecting body iron requirements. The iron absorbed is distributed to various body tissues and organs bound to the plasma protein transferrin (Tf) [2]. Quantitatively, most iron is incorporated into erythrocytes for heme synthesis, but all body cells require some iron to meet their metabolic requirements.…”

“…Small amounts (1-2 mg) of iron are also lost daily from the body by processes such as sloughing of intestinal mucosal and skin cells, and in the urine and bile. Women have additional losses associated with menstruation, and consequently their daily iron requirements are somewhat higher than those of men [1][2][3].…”

“…Divalent metal ion transporter 1 (DMT1) carries the released iron across the endosomal membrane into the cytoplasm of the cell [8], where it can be utilized for metabolic purposes. Internalized iron not required immediately for biosynthesis is sequestered within the cytosolic protein ferritin (Ft) [2,9]. Most tissues are able to divest themselves of iron, a process mediated predominantly by the iron transporter ferroportin (FPN) [10].…”

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

“…To be absorbed, the dietary iron, which is mainly in the poorly soluble and absorbable ferric state, must be reduced from the ferric to the ferrous state by ferric reductase, expressed on the luminal surface of the duodenum. The ferrous iron is then taken up by a specialized luminal iron transporter, called divalent metal transporter-1 (DMT1), and it may be stored within the mucosal cell as ferritin or transported across to the plasma via ferroportin [30][31][32]. Conversely, the HFE protein is found in the crypt cells of the duodenum where it forms a complex with transferrin receptor 1 (TfR1), which is the receptor by which cells acquire ironloaded transferrin.…”

“…In hereditary hemochromatosis, the mutant HFE may impair TfR1-mediated uptake of transferrin-bound iron into crypt cells, leading to an iron deficiency in duodenal crypt cells. The consequence is an over expression of DMT1, which in turn is responsible for enhanced iron absorption in villous cells of the small intestine [9,32]. However, this pathogenic model of HFE-related hereditary hemochromatosis, also called crypt-programming model, has been challenged after the discovery of hepcidin, a peptide that has a key role in human iron metabolism and which is associated with juvenile hereditary hemochromatosis [9,[34][35][36].…”