Two to Tango: Regulation of Mammalian Iron Metabolism

Abstract

Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. Iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the iron exporter ferroportin, and another that predominantly controls cellular iron metabolism through iron-regulatory proteins that bind iron-responsive elements in regulated messenger RNAs. We describe how the two distinct systems function and how they "tango" together in a coordinated manner. We also highlight some of the current questions in mammalian iron metabolism and discuss therapeutic opportunities arising from a better understanding of the underlying biological principles.

Dilution of candidates: the case of iron-related genes in restless legs syndrome

“…Besides the three NBIA genes (see OMIM database), this set comprised 35 genes listed by the HealthIron 17 consortium and another 72 genes that have been discussed in recent reviews on iron metabolism. 15,18 The complete list is given in Supplementary Table 1. Of the SNPs within the 4 Mbintervals surrounding these genes by 2 Mb in both directions, 18 had P-values below the cut-off level (ignoring the SNPs in high LD with a SNP in one of the already known RLS genes).…”

“…In this step, we applied age, sex, and the first four axes of variation resulting from MDS analysis as covariates. We performed a candidate-based analysis focusing on SNPs within 4 Mb intervals (2 Mb in each direction) surrounding each of 111 genes (see Supplementary Table 1) known to be involved in iron metabolism 15,17,18 or in neurodegeneration with brain iron accumulation (NBIA), NBIA1-NBIA3 (PANK2, PLA2G6, and FTL). From that set of SNPs, we selected those with a nominal P-value o5 Â 10 À4 for replication.…”

The role of lysosomes in iron metabolism and recycling

“…The iron regulatory proteins 1 and 2 (IRP1 and IRP2) control the uptake and storage of iron at the cellular level by interacting at the translational level with ironresponsive elements (IREs) on RNA transcripts that code for the H-and L-ferritin subunits, TfR1, DMT1, mitochondrial aconitase and 5-aminolevulinate synthase (Hentze et al, 2010, Rouault, 2006. Depending on their degree of iron binding, IRPs attach themselves to IREs and thereby prevent or stabilize translation of the above proteins that regulate uptake, storage, transport and metabolism of intracellular iron.…”

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

“…In addition, plasma iron levels are tightly regulated by the action of the peptide hormone hepcidin. Hepcidin, which is mostly secreted in the liver, promotes the degradation of the iron exporter ferroportin expressed on the surface of iron-releasing cells, thus reducing intestinal iron absorption and its mobilization from hepatic stores, and promoting iron retention within erythrophagocyto-sing macrophages [2]. Nevertheless, mutations in the genes encoding hepcidin (Hamp) or other key regulatory proteins like HFE, hemojuvelin or transferrin receptor 2 result in inappropriately low hepcidin levels and lead to the development of Hereditary Hemochromatosis (HH), an autosomal recessive disorder that is characterized by excessive absorption of dietary iron and its deposition in the parenchymal cells of the liver and other body organs [3].…”

“…However, iron in excess is detrimental, as it can catalyze the formation of damaging radical species via Fenton-type reactions [1]. In normal conditions, iron toxicity is prevented by the binding of extracellular iron in the plasma to transferrin and by storage of intracellular iron in a protein with high storage capacity, ferritin [2]. In addition, plasma iron levels are tightly regulated by the action of the peptide hormone hepcidin.…”