Cellular Iron Metabolism –The IRP/IRE Regulatory Network
Ricky S. Joshi, Erica Morán and Mayka Sánchez

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1. Introduction
General Overview of iron homeostasis
Iron is the most abundant transition metal in cellular systems and is an essential micronutrient required for many cellular processes including DNA synthesis, oxidative cell metabolism, haemoglobin synthesis and cell respiration. Despite iron being an absolute requirement for almost all organisms, caution should be taken with an inappropriate disequilibrium in iron levels because excess iron is toxic and a lack of it leads to anaemia.
As a transition metal, iron can exist in various oxidation states (from -2 to +6). Usually, iron exists and switches between two different ionic states (Fe+2 and Fe+3). Iron in the reduced state is known as ferrous iron and has a net positive charge of two (Fe+2). In the oxidized state it is known as ferric iron and has a net positive charge of three (Fe+3). This electron switch property of iron as a metal element allows it to be used as a cofactor by many enzymes involved in oxidation-reduction reactions and also confers its toxicity. Iron toxicity relates to the intracellular labile iron pool (LIP), a pool of transitory, chelatable (i.e. free) and redox-active iron that can catalyze the formation of oxygen-derived free radicals via the
Fenton reaction. Iron-catalyzed oxidative stress causes lipid peroxidation, protein modifications, DNA damage (promoting mutagenesis) and depletion of antioxidant defences.
Iron containing proteins can be classified into 3 groups (for an extensive revision see (Crichton, 2009)):
Haemoproteins, in which iron is bound to four ring nitrogen atoms of a porphyrin molecule called haem and one or two axial ligands from the protein. Examples of haemoproteins are the oxygen transport protein haemoglobin, the muscle oxygen storage protein myoglobin, peroxidases, catalases and electron transport proteins such as the cytochromes a, b and c.
Iron-sulphur proteins are proteins that contain iron atoms bound to sulphur forming a cluster linked to the polypeptide chain by thiol groups of cysteine residues or to non-protein structures by inorganic sulphide and cysteine thiols. Examples of iron-sulphur proteins are the ferredoxins, hydrogenases, nitrogenases, NADH dehydrogenases and aconitases.
Non-haem non iron-sulphur proteins, these proteins can be of three types:
Mononuclear non-haem iron enzymes such as catechol or Rieske dioxygenases, alpha-keto acid dependent enzymes, pterin-dependent hydrolases, lipoxygenases and bacterial superoxide dismutases
Dinuclear non-haem iron enzymes, also known as diiron proteins, like the H-ferritin chain, haemerythrins, ribonucleotide redictase R2 subunit, stearoyl-CoA desaturases and bacterial monoxygenases
Proteins involved in ferric iron transport, for instance the transferrin family that includes serotransferrin, lactotransferrin, ovotransferrin and melanotransferrin and are found in physiological fluids of many vertebrates.
As previously mentioned, many proteins involved in very different cellular pathways contain iron. Therefore, cells require iron to function properly. However, mammals have no physiological excretion mechanisms to release an excess of iron and consequently, iron homeostasis must be tightly controlled on both the systemic and cellular levels to provide just the right amounts of iron at all times. If an adequate balance of iron is not achieved, it will cause a clinical disorder. Iron is therefore crucial for health. Iron deficiency leads to anaemia —a major world-wide public health problem— and iron overload is toxic and increases the oxidative stress of body tissues leading to inflammation, cell death, system organ dysfunction, and cancer (Hentze et al., 2010).
Systemic iron homeostasis is regulated by the hepcidin/ferroportin system in vertebrates (Ganz & Nemeth, 2011). Hepcidin is a liver-specific hormone secreted in response to iron loading and inflammation and is the master regulator of systemic iron homeostasis.
Increased hepcidin levels result in anaemia while decreased expression is a causative feature in most primary iron overload diseases. Transcription of hepcidin in hepatocytes is regulated by a variety of stimuli including cytokines (TNF-TNF-

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