Regulating Iron Metabolism Essay
Iron is an essential nutrient for many organisms as it aids in numerous cellular processes such as oxygen transport and DNA synthesis. In overload, iron generates free radicals that damage both proteins and lipids. On the other hand, a deficiency of iron undermines cell proliferation.
Iron metabolism: an outline
An adult manages to take up around 1-3mg of iron a day, in order to make up for any losses through sweat, urine and dying red cells. Non-heme iron is taken up by red cells through bivalent metal transporters, also heme iron is taken up by red cells though an undefined mechanism. Regulating Iron Metabolism Essay.
Regulation of iron metabolism
Keeping a constant cellular iron content is important and therefore the body has developed precise mechanisms for the regulation of uptake storage and export of iron. The Iron-Responsive Element (IRE)/ Iron Regulatory Protein (IRP) regulatory mechanism consists of a mechanism responsible for regulating post-transcriptional gene expression to maintain iron homeostasis. It involves two RNA binding proteins Iron-regulatory protein 1&2 (IRP 1, IRP 2) and a regulatory RNA elements known as Iron Responsive Elements.
IRE/IRP interactions control the expression of mRNA sequences that encode for proteins responsible for iron acquisition (divalent metal transporter 1 and transferrin receptor 1), storage of iron (H-ferritin and L-ferritin) iron utilization (erythroid 5-aminolevulinic acid synthase), energy (mitochondrial aconitase), and iron export (ferroportin) (Muckhentaler, et al., 2008).
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The processes responsible from binding IRP1 and IRP2 to IRE are regulated mainly by iron levels, although other stimuli do exist, such as hypoxia and nitric oxide.Regulating Iron Metabolism Essay. In cells which have high iron levels, the IRP/IRE binding activity is low as IRP 1 & 2 are incapable of binding to IRE. In such conditions, IRP1 would set up an iron-sulphur cluster (Fe-S) which in turn transforms into cytosolic aconitase, whereas IRP2 would become degraded through the action of the proteosome. This means that only in iron-depleted cells would the IRP proteins bind to IRE.
Both IRP 1 & 2 hinder translation initiation when bound to the 5’Untranslated Region of IRE, by inhibiting the binding of the small ribosomal sub-unit to the mRNA sequence (Muckenthaler, et al., 1998). In addition, when IRP1 is bound to a cap proximal IRE, and hence the cap binding complex (eIF4F) is produced. At this point the small ribosomal sub-unit does not incorporate in the presence of IRP1 which hinders any interactions needed between the cap binding complex and the small ribosomal sub-unit. The association of IRP 1 with the 3’IRE of transferrin receptor 1 reduces its turnover by hindering the cleavage of a restriction site and eventually its mRNA degradation (Binder, et al., 1994). The mechanism that stabilizes IRP mRNA has not yet been well investigated for other 3’IRE containing mRNA’s like CDC14A and DMT1, which contain one 3’IRE site and could require other factors in order to be regulated. Therefore, it can be said that the binding of IRP 1 & 2 ensures iron balance and no over expression of target mRNA molecules.
The IRP/IRE system was primarily described as a non-complex post-transcriptional gene expression which regulates the formation of ferritins and transferrin receptor 1. The discovery of other mRNA sequences associated with this system has increased the complexity and has enhanced the role of IRP proteins to connect different pathways, which are regulated by iron metabolism.
Assessment of Iron Status
Iron studies are a group of tests that are performed in order to evaluate the status of the iron stores as well as the concentration of iron in serum. Tests that are performed when an Iron profile is ordered may include:
- Serum iron
- Total Iron-Binding Capacity (TIBC) and/or Unsaturated Iron-Binding Capacity (UIBC)
- Transferrin
- Ferritin
- Transferrin receptor
- Transferrin Saturation
Serum iron is a measure of the amount of iron present in blood and usually does not diminish until iron stores are depleted.Regulating Iron Metabolism Essay. It is ordered normally as a follow-up when low levels of haemoglobin and haematocrit are observed on a complete blood count. An increased level of iron can be due to ingestion of iron (e.g. food or medication) or ineffective erythropoiesis. On the other hand low iron levels might be the result of: infection, menstruation, inflammation, malignancy or iron deficiency.
Total Iron-Binding Capacity (TIBC) is also used to measure the status of iron in blood. It can be either measured or else calculated based on the level of transferrin in the blood. TIBC and serum iron can then be used to calculate percentage transferrin saturation, which is a much better index for iron status than serum iron or TIBC alone, using the flowing calculation:
The 26.1 value is used as a constant to convert Transferrin to an equivalent TIBC concentration.
UIBC is normally used as an alternative to TIBC.
Percentage transferrin saturation (TSAT) is a measurement of the amount of iron which is effectively bound to transferrin, therefore indicting the amount of iron which is available to sustain erythropoiesis. A low TSAT may be indicative of infection, erythropoiesis, inflammation or iron deficiency. Whereas, an elevate value might mean haemochromatosis, liver disease, ineffective erythropoiesis or recent ingestion of dietary iron.
Transferrin is the plasma protein responsible for the transport of iron inside the body. It is also habitual to test for transferrin (apart from TIBC or UIBC) as this is a better indicator of the patient’s nutritional status and to some extent an indicator of liver function, since transferrin is produced in the liver. Low levels of transferrin can be observed with liver disease, however transferrin may also drop in malignant tumors and if not enough dietary protein is taken up. On the other hand, high levels can be observed with iron deficiency and during pregnancy.
Iron can be stored intracellularly in the form of ferritin. Ferritin is a protein which stores iron in a non-toxic form. It is a sizeable molecule with a core of ferric hydroxide phosphate. It is considered to be the best indicator of iron stores in the body. Low levels of ferritin are normally indicative of iron deficiency or a response to therapy involving erythropoietin, whereas high levels might be due to inflammation, malignancy or infection. Regulating Iron Metabolism Essay.
Soluble transferrin receptor (sTFR) does not necessarily feature in an iron panel; however it is worth mentioning since it helps distinguishing between iron deficiency anemia and anemia of chronic disease. It is normally ordered in the case that an iron panel does not give enough information to reach a conclusive diagnosis. Usually to evaluate the status of iron stores ferritin is the preferred indicator. However, it is an acute phase reactant, meaning that it can give a falsely elevated value with inflammation or chronic disease. Seeing a, sTFR is not an acute phase reactant, it can be used as an alternative in case chronic disease is suspected.
Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O’Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.
Introduction
Iron is one of the most abundant elements on Earth and essential to almost all organisms. Iron exists in a wide range of oxidation states, −2 to +7. Chemically, the most common and biologically relevant oxidation states of iron are +2 and +3, ferrous (Fe2+) and ferric (Fe3+) iron. Ferrous (Fe2+) iron is more soluble and bioavailable than its ferric (Fe3+) form and that the interchangeability of these two ionic forms of iron via oxidation/reduction are essential for the function of many cellular proteins. Regulating Iron Metabolism Essay. Levels of iron in the body are strictly controlled through finely tuned complex mechanisms, to prevent the cytotoxicity that is induced by accumulation of this metal and to allow physiologically tolerable iron levels to serve as a critical catalytic component of many proteins and enzymes, called metalloproteins.
Metalloproteins can directly bind iron or use iron-containing complexes such as heme or iron-sulfur (Fe-S) clusters. Such proteins have diverse and essential processes within the cell, including oxygen carrying (hemoglobin), oxygen storage (myoglobin), energy production (cytochrome-C), cellular metabolism (amino acid oxidases, fatty acid desaturases), detoxification (cytochrome P450, catalase), and host defense (myeloperoxidase, nitric oxide synthase, IDO, NAPH oxidase) (Muckenthaler et al., 2017). Although the chemistry of iron will not be discussed here in detail, Fenton/Haber-Weiss chemistry is a very important reaction with widespread effects on biological systems under normal and pathophysiological conditions: ferrous (Fe2+) iron reacts with hydrogen peroxide to form the hydroxyl ion (OH−), the hydroxyl radical (OH•) and ferric (Fe3+) iron (Koskenkorva-Frank et al., 2013). The OH• radical is a non-selective, highly toxic oxidant. As mitochondria produce ATP by oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) by-products such as superoxide are generated from the electron transport chain (ETC). Superoxide radicals can reduce and liberate Fe3+ from ferritin or liberate Fe2+ from Fe-S clusters (see below). Biologically-available iron not sequestered is thus a dangerous source of damaging radicals (Breuer et al., 2008). It is important to note that not all free radicals are detrimental and not all antioxidants are beneficial. Normal physiology is a balance between the two: antioxidants maintain levels of ROS that permit them to perform useful biological functions, such as neutrophil-mediated killing of phagocytosed bacteria or enhanced T cell proliferation after TCR stimulation, while minimizing by-stander damage. However, under pathophysiological conditions, such as enhanced mitochondrial stress, this balance gets perturbed to the detriment of the organism. Regulating Iron Metabolism Essay.
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Iron is essential for many physiological processes in the body including erythropoiesis, immune function and host defense, as well as essential cellular activities such as DNA replication and repair, mitochondrial function including OXPHOS and enzymatic reactions which require iron as a cofactor. Extensive research by many groups has unveiled the regulatory network governing iron homeostasis in the body and inside the cell, as well as the links between disturbances of iron homeostasis and disease. Iron deficiency is the most common pathology of iron homeostasis, eventually resulting in iron deficiency anemia, the most frequent anemia worldwide (Camaschella, 2015). The second most frequent anemia, anemia of inflammation (also called anemia of chronic disease), largely results from inflammation-driven retention of iron in certain immune cells, resulting in iron-limited erythropoiesis (Weiss et al., 2019). This latter pathology reflects the complex regulatory interactions between iron and the immune system, which emerged evolutionary from a strategy of the organism to withhold nutrient iron from invading pathogens, a defense mechanism known as nutritional immunity. Regulating Iron Metabolism Essay. Accordingly, iron trafficking is controlled by cytokines and acute phase proteins, whereas the metal itself promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism, as we will discuss later (Ganz and Nemeth, 2015; Soares and Weiss, 2015). Thus, imbalances in iron homeostasis are prevalent in infections, cancer as well as autoimmunity, and its pathophysiological or therapeutic modulation impacts on the outcome of such diseases. Evolution reveals its mastery in the way the body and immune cells strike a balance between iron supply and demand with pathways tightly regulating iron levels extra- and intra-cellularly, from its uptake, use, storage, and export, collectively referred to as the iron cycle (Figure 1, Table 1). In the next sections we will describe the various stages of the iron cycle and give an overview of how iron levels are monitored and regulated inside the cell. This cellular regulation of iron is applicable to practically every cell in the body, including all immune cells. Regulating Iron Metabolism Essay.
