Molecular mediators governing iron-copper interactions

Abstract

Given their similar physiochemical properties, it is a logical postulate that iron and copper metabolism are intertwined. Indeed, iron-copper interactions were first documented over a century ago, but the homeostatic effects of one on the other has not been elucidated at a molecular level to date. Recent experimental work has, however, begun to provide mechanistic insight into how copper influences iron metabolism. During iron deficiency, elevated copper levels are observed in the intestinal mucosa, liver, and blood. Copper accumulation and/or redistribution within enterocytes may influence iron transport, and high hepatic copper may enhance biosynthesis of a circulating ferroxidase, which potentiates iron release from stores. Moreover, emerging evidence has documented direct effects of copper on the expression and activity of the iron-regulatory hormone hepcidin. This review summarizes current experimental work in this field, with a focus on molecular aspects of iron-copper interplay and how these interactions relate to various disease states.

Keywords: ceruloplasmin, hephaestin; copper-transporting ATPase1; divalent metal-ion transporter 1; ferroportin 1; intestine; liver.

Figure 1

Iron-copper (Fe-Cu) interactions and whole-body homeostasis of both minerals. Physiological aspects of iron and copper homeostasis are shown, with points of interplay between the two metals indicated by circled numbers. Copper transport is shown with green arrows and lines; iron movement is shown in a dark red color. Both minerals are absorbed in the proximal small intestine. ➀ Several points where copper may influence iron transport are shown in the inset of a duodenal enterocyte (asterisks) (additional details are depicted in Figure 2). After transport to the liver via the portal vein, copper is mainly incorporated into ceruloplasmin (CP) in hepatocytes. ➁ Copper exits the liver principally as part of CP, which functions predominantly as a ferroxidase to promote iron release from certain tissues. Excess body copper is lost via excretion in bile. ➂ Iron is bound to transferrin (TF) in the portal blood and either stored in hepatocytes bound to ferritin or released into the blood, where it is distributed as diferric-TF. ➃ Iron-copper interactions in the liver are well established. Iron release from liver is a copper-dependent process as hepatic iron accumulation typifies copper deficiency. Moreover, copper accumulates in the liver during iron deprivation. ➄ Most Fe-TF is taken up by developing erythrocytes in the bone marrow to support hemoglobin (Hb) synthesis. Iron utilization by these cells is copper dependent, although the precise mechanism is unclear. ➅ Iron is also assimilated by other tissues, including the brain and the central nervous system, where iron release requires glycosylphosphatidylinositol (GPI)-CP. ➆ Another copper-containing ferroxidase (zyklopen) may also be required for iron flux in the placenta. ➇ Iron contained within senescent red blood cells is recovered and stored by reticuloendothelial (RE) macrophages. Iron release from RE macrophages requires copper, again involving CP or possibly GPI-CP. ➈ Iron homeostasis is controlled by the liver-derived peptide hormone hepcidin, which alters iron flux by blocking iron absorption in the intestine and iron release from stores. Hepcidin is activated by copper, exemplifying another point of iron-copper interaction. There are no active, regulated excretory mechanisms for iron in humans, but some iron is lost by desquamation of skin cells and exfoliation of enterocytes, and by blood loss. Abbreviations: CTR1, copper transporter 1; CYBRD1, cytochrome b reductase 1; DMT1, divalent metal-ion transporter 1; HEPH, hephaestin; TGN, trans-Golgi network.

Figure 2

Iron-copper homeostasis and interactions in duodenal enterocytes. An intestinal epithelial cell (IEC) is depicted with the iron and copper transport machinery. Points of interaction between the two minerals are indicated by circled numbers. ➀ Both metals have to be reduced for absorption, and cytochrome B reductase 1 (CYBRD1) (and/or other reductases) may act upon both ions on the apical surface. ➁ Once reduced, iron enters IECs via divalent metal-ion transporter 1 (DMT1) along with cotransported protons. DMT1 may also transport copper, perhaps only during iron deficiency (FeD). The electrochemical proton gradient across the brush-border membrane (BBM) is maintained via the action of an apical sodium-hydrogen exchanger (NHE) and the basolateral membrane (BLM) Na⁺/K⁺ ATPase (not shown). Absorbed iron may be transported into mitochondria for metabolic use, stored in ferritin or ➂ transported across the BLM by ferroportin 1 (FPN1). The expression and/or activity of FPN1 may be influenced by copper. ➃ Ferrous iron must then be oxidized by the multicopper ferroxidase hephaestin (HEPH) or other ferroxidases (not depicted) to allow binding to transferrin (TF). Copper, after reduction at the BBM, enters cells via copper transporter 1 (CTR1) and is then distributed by intracellular chaperones. ➄ Copper enters the trans-Golgi network (TGN) via ATP7A for use in cuproenzyme synthesis or exits cells also via ATP7A, which traffics to the basolateral surface when copper is in excess. ATP7A is strongly induced during iron deprivation, suggesting that it may affect iron metabolism in enterocytes. Copper is spontaneously oxidized and then binds to serum carriers (e.g., albumin) for transport to the liver. Abbreviations: ATOX1, antioxidant 1 copper chaperone; CCS, copper chaperone for superoxide dismutase 1 (SOD1); MT, metallothionein.

Figure 3

Iron-copper homeostasis and interactions in hepatocytes. ➀ Hepatocytes regulate systemic iron homeostasis by producing and excreting the iron-regulatory peptide hormone hepcidin. Copper may influence hepcidin expression and/or activity. These cells control overall body copper homeostasis as well by regulating copper excretion in bile. Hepatocytes assimilate iron via endocytosis of Fe-transferrin (TF) via transferrin receptor (TFR)1/2. In endosomes, iron is released from TF by the action of a hydrogen ATPase and is then transported into the cytosol by divalent metal-ion transporter 1 (DMT1) or zinc transporter ZIP14. ➁ The endosomal reductase [perhaps six-transmembrane epithelial antigen of the prostate 3 (STEAP3) may influence intracellular iron and copper metabolism. Iron is used in cells, stored in ferritin, or ➂ exported by ferroportin 1 (FPN1) (which may be influenced by copper levels). ➃ After reduction by a potentially multifunctional metalloreductase, cuprous (Cu⁺) copper is taken up via copper transporter 1 (CTR1) and distributed within cells by chaperones. Antioxidant 1 copper chaperone (ATOX1) delivers copper to copper-transporting ATPase 2 (ATP7B), which pumps copper into the trans-Golgi network (TGN) for ➄ incorporation into the multicopper ferroxidases (FOXs) glycosylphosphatidylinositol (GPI)-ceruloplasmin (CP) and CP, which oxidize iron released from hepatocytes (and other cells) to permit binding to TF. ATP7B also mediates copper excretion across the canalicular membrane into bile. ATP7B activity is regulated by copper metabolism MURR1 domain (COMMD1) and indirectly by a ubiquitin ligase [X-linked inhibitor of apoptosis protein (XIAP)], which mediates COMMD1 proteasomal degradation. Abbreviation: CCS, copper chaperone for superoxide dismutase 1.

Figure 4

Iron-copper homeostasis in erythroid cells. Developing erythroid cells acquire iron via the Fe-transferrin (TF)/transferrin receptor 1 (TFR1) cycle. ➀ An endosomal reductase [perhaps a multifunctional six-transmembrane epithelial antigen of the prostate (STEAP) protein] reduces ferric iron prior to divalent metal-ion transporter 1 (DMT1)-mediated transport into the cytosol. Most iron in these cells enters the mitochondria, where it is transported into the matrix via mitoferrin. The chaperone, frataxin (FXN), may deliver iron to the sites of Fe-S cluster assembly and heme synthesis. Fe-S clusters and heme are incorporated into proteins comprising the electron transport chain complexes I–IV. ➁ After reduction at the cell surface by a potentially multifunctional reductase, most copper taken up by erythroid cells via copper transporter 1 (CTR1) is delivered to SOD1 by CCS (copper chaperone for superoxide dismutase 1). ➂ Copper is also directed to the mitochondrion for incorporation into complex IV [cytochrome C oxidase (CCO)], which also has two iron-containing heme moieties. Mitochondrial copper is delivered to CCO by the cytochrome C oxidase copper chaperone, COX17. Copper deficiency may ➃ decrease the assimilation of iron from Fe-TF, ➄ impair uptake of iron by mitochondria, and/or ➅ reduce heme synthesis, exemplifying additional points of possible iron-copper interaction.