Question

Describe the interplay of the microminerals iron and copper in metabolism?

Answer 1

Among the essential trace minerals, iron and copper are unique as they exist in two oxidation states in biological systems and can potentiate the formation of damaging oxygen free radicals when in excess. Deficiencies of both nutrients are also associated with significant physiological perturbations. Given the potential adverse effects of too much or too little iron or copper, their homeostasis is tightly controlled at the cellular and organismal levels by local and systemic mediators. The reactive nature of these metal ions underlies important biological functions related to electron transfer (i.e., redox) reactions, in which both metals function as enzyme cofactors. Moreover, given their similar physiochemical properties, including comparable atomic radii and electrical charges, it is not surprising that biologically-relevant interactions between iron and copper have been frequently noted in mammals .

Iron extraction from the diet in the proximal small intestine is tightly controlled since no active, regulated mechanisms exist in humans to excrete excess iron (although rodents do have a limited capacity to excrete iron in bile). Iron homeostasis is regulated at the whole-body level by the hepatic, peptide hormone hepcidin (HEPC). HEPC is released when body iron stores increase and during infection and inflammation, and it functions to reduce serum iron concentrations. It accomplishes this by binding to the iron exporter, ferroportin 1 (FPN1), which is expressed on the surface of cells that absorb and store iron, causing its internalization and degradation . Additional transcriptional and posttranscriptional mechanisms also exist at the cellular level to locally regulate iron homeostasis. Collectively, these homeostatic loops modulate the expression of genes encoding iron metabolism-related proteins, including iron transporters and an iron reductase (i.e., a “ferrireductase”). One such mechanism involves the transactivation of genes in enterocytes by a hypoxia-inducible factor-2α (HIF2α) during iron deprivation (with concurrent hypoxia). Another regulatory mechanism acts posttranscriptionally to control mRNA levels within many cells via interaction of a stem-loop structure within the transcripts [i.e., iron-responsive elements (IREs)] with cytosolic, iron-sensing proteins [called iron-regulatory proteins (IRPs)]. These interactions can either inhibit translation of a message or increase its stability, leading to the production of more protein. Intracellular modulation of “free,” or unbound, iron levels also occurs via interaction with ferritin, which sequesters excess iron, thus rendering it unreactive.

Iron-copper interactions in humans were perhaps first described in the middle of the nineteenth century in industrialized Europe. As described in the early literature, a disease referred to as the “greening sickness” or “chlorosis” was common among factory workers at the time . Young women, in particular, were most likely to suffer from this disorder. Common symptoms included lethargy and decreased work capacity, paleness, and amenorrhea Based upon descriptions from publications at the time, it is a logical prediction that chlorosis was in actuality iron-deficiency anemia, which commonly afflicts young women of childbearing age even today. Although this pathological condition was common in the general population, young women working in copper factories did not develop chlorosis, suggesting that copper exposure was somehow protective. There were reports of young women breastfeeding their infants with copper salts splashed across their bodies. These decades’ old observations provide the earliest examples of possible interactions between iron and copper. Based upon the current state of knowledge in this area of scientific research, it is a logical postulate that copper exposure enhanced absorption of dietary iron or potentiated iron utilization by developing erythrocytes in the bone marrow in these female factory workers (thus preventing the development of anemia). These possibilities seem most likely given that intestinal iron absorption ultimately determines overall body iron levels (since no excretory mechanism exists in humans), and that most iron is utilized for hemoglobin production in red blood cells. Another possibility is that copper depletion caused chlorosis. This seems plausible since copper deficiency causes an anemia that is indistinguishable from the anemia associated with ID. Although these observational reports do not clarify the specific underlying cause of chlorosis, they nonetheless nicely exemplify the longstanding historical appreciation of the intersection of iron and copper metabolism as it relates to human physiology and pathophysiology.

Highlights points of intersection between iron and copper metabolism from absorption in the gut, to utilization by body cells and tissues, to regulated (for copper) and unregulated losses (for both minerals). Both minerals are absorbed from the diet in the duodenum, with efficiency of absorption being matched to physiologic demand. Hormonal control of iron absorption has been described, but no copper-regulatory hormones have been identified to date. The liver-derived, peptide hormone HEPC modulates iron efflux from duodenal enterocytes by blocking iron export via FPN1. The mechanism involves HEPC binding to FPN1, which leads to endocytosis and eventual degradation of the FPN1 protein in the lysosome . HEPC also blocks iron release from stores in reticuloendothelial (RE) macrophages of the bone marrow, spleen, and liver (Kupffer cells), hepatocytes, and placental trophoblasts, by a similar mechanism. The overall effect of HEPC then is to lower serum iron concentrations, which occurs when body iron levels are high, and during infection and inflammation (as part of the acute-phase response). Subsequent to passage through enterocytes into the interstitial fluids, iron is bound by transferrin (TF) and copper by mainly albumin, which facilitates delivery of both minerals to the liver via the portal blood circulation. Diet-derived, hepatic iron may be utilized for metabolic purposes, stored in hepatocytes (in ferritin), or released into the blood where it again is bound by TF . Similarly, hepatic copper may be utilized by liver cells, stored in hepatocytes (in MT), or biosynthetically incorporated into ceruloplasmin (CP). Most copper exits the liver as CP-copper, but other copper exporters release free copper into the blood (which binds to serum proteins, such as albumin). Iron and copper are then widely distributed throughout the body, as all body cells require these minerals for metabolic purposes. The bone marrow is an “iron sink” as most body iron is utilized for Hb production in developing erythrocytes. Copper, however, does not concentrate into one particular tissue like iron.

Humans and other mammals require iron for a variety of biological functions. ID is thus associated with significant pathophysiologic perturbations. Iron-containing proteins mediate energy (i.e., ATP) production, gas transport in the blood, and regulation of cell growth and differentiation and gene expression. Moreover, iron, when in excess, is toxic. Body iron levels are therefore controlled to ensure that adequate iron is available, while preventing excess accumulation in tissues and cells. Regulatory mechanisms that govern iron absorption, and storage and recycling, have developed over evolutionary time in humans. Iron is required for the activity of numerous proteins, where it facilitates important functions (e.g., electron transfer in redox reactions). Additionally, some proteins bind iron but have no known enzymatic function. These proteins contain iron in heme, in iron-sulfur clusters, or in other chemical configurations . Examples of these proteins include hemoglobin and myoglobin, which function in oxygen transport. Some iron-sulfur cluster-containing proteins (e.g., cytochromes of the electron transport chain) mediate energy production, by transferring electrons. Heme-containing proteins, such as cytochrome P450 complexes, also mediate electron transfer reactions. Iron transporters, such as DMT1 and FPN1, transiently bind iron and facilitate its movement across cellular membranes. Given the importance of these example iron-dependent enzymes (and others not mentioned) in normal physiology.

Erythroid Cells

Erythroid cells are the most avid consumers of iron in the body. Each day, erythroid precursors of the bone marrow take up 20-25 mg of iron as they mature into erythrocytes. Unlike hepatocytes or enterocytes, which can rapidly assimilate NTBI, erythroid cells can acquire iron only from Fe-TF . At the cell surface, TFR1 binds to circulating Fe-TF, leading to internalization of the Fe-TF/TFR1 complex into endosomes. The acquired ferric iron is then reduced to Fe2+ by Steap3 and transported into the cytosol by DMT1. That Steap3 serves as the endosomal ferrireductase in erythroid cells was revealed by studies of Steap3 mutant and Steap3-null animals.The essential role of DMT1 in iron assimilation by erythroid cells was demonstrated by mice engineered to lack Dmt1 in hematopoietic cells,as well as by studies of reticulocytes from anemic Belgrade rats, which express a poorly functional mutant form of the protein.

Brain

Brain metal homeostasis is carefully regulated by an elegant series of influx and efflux transporters because, while essential, excess copper and iron lead to neuropathology. These transporters are especially critical in brain were metal flux requires passage through multiple membranes of the neurovascular unit, often called blood-brain-barrier (BBB). There is another cellular barrier separating cerebral spinal fluid (CSF) from blood lined by polarized cells of the choroid plexus, often called blood-CSF-barrier (BCB). Both copper and iron transporters are enriched in cells lining these barriers compared to brain parenchyma.

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