Iron regulatory proteins and their role in controlling iron metabolism

Metallomics ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 232-243 ◽  
Author(s):  
Lukas C. Kühn
Keyword(s):  
Iron Metabolism ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Regulatory Proteins ◽  
Feedback Mechanisms ◽  
Iron Regulatory Proteins ◽  
Body Iron ◽  
Transcriptional Feedback

Cellular and body iron homeostasis are regulated by iron-sensing and post-transcriptional feedback mechanisms, which control iron uptake, release, storage and heme biosythesis.

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

Abstract The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

Iron Regulatory Proteins in Systemic Iron Metabolism and Erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-22-SCI-22
Author(s):  
Matthias W. Hentze
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Mutant Mouse ◽  
Conflicts Of Interest ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Regulatory Systems ◽  
Biology I ◽  
Mouse Lines

Abstract Abstract SCI-22 Imbalances of iron homeostasis account for some of the most common human diseases. Pathologies can result from both iron deficiency or overload. The hepcidin/ferroportin and the IRE/IRP regulatory systems balance systemic and cellular iron metabolism, respectively, and understanding their points of intersection and crosstalk represents a major challenge in iron biology. I will discuss an emerging picture from studies with different mutant mouse lines according to which the “cellular” IRE/IRP system determines “set points” via its targets (including ferroportin and HIF2α). These are then subject to modulation via hepcidin in response to systemic cues. Disclosures: No relevant conflicts of interest to declare.

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

scholarly journals Iron-regulatory proteins: molecular biology and pathophysiological implications

2007 ◽  
Vol 9 (33) ◽  
pp. 1-13 ◽  
Author(s):  
Gaetano Cairo ◽  
Stefania Recalcati
Keyword(s):  
Cell Growth ◽  
Molecular Biology ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Regulatory Proteins ◽  
Cellular Functions ◽  
Major Health ◽  
Iron Regulatory Proteins ◽  
Human Disorders ◽  
Apoptosis And Inflammation

AbstractIron is required for key cellular functions, and there is a strong link between iron metabolism and important metabolic processes, such as cell growth, apoptosis and inflammation. Diseases that are directly or indirectly related to iron metabolism represent major health problems. Iron-regulatory proteins (IRPs) 1 and 2 are key controllers of vertebrate iron metabolism and post-transcriptionally regulate expression of the major iron homeostasis genes. Here we discuss how dysregulation of the IRP system can result from both iron-related and unrelated effectors and explain how this can have important pathological consequences in several human disorders.

scholarly journals Bacterial effector targeting of a plant iron sensor facilitates iron acquisition and pathogen colonization

2021 ◽  
Author(s):  
Yingying Xing ◽  
Ning Xu ◽  
Deepak D Bhandari ◽  
Dmitry Lapin ◽  
Xinhua Sun ◽  
...  
Keyword(s):  
Pseudomonas Syringae ◽  
Iron Uptake ◽  
Iron Acquisition ◽  
Iron Accumulation ◽  
Regulatory Proteins ◽  
Mineral Nutrient ◽  
Effector Protein ◽  
Iron Regulatory Proteins ◽  
Protein Levels ◽  
Pathogen Colonization

Abstract Acquisition of nutrients from different species is necessary for pathogen colonization. Iron is an essential mineral nutrient for nearly all organisms, but little is known about how pathogens manipulate plant hosts to acquire iron. Here, we report that AvrRps4, an effector protein delivered by Pseudomonas syringae bacteria to plants, interacts with and targets the plant iron sensor protein BRUTUS (BTS) to facilitate iron uptake and pathogen proliferation in Arabidopsis thaliana. Infection of rps4 and eds1 by P. syringae pv. tomato (Pst) DC3000 expressing AvrRps4 resulted in iron accumulation, especially in the plant apoplast. AvrRps4 alleviates BTS-mediated degradation of bHLH115 and ILR3(IAA-Leucine resistant 3), two iron regulatory proteins. In addition, BTS is important for accumulating immune proteins Enhanced Disease Susceptibility1 (EDS1) at both the transcriptional and protein levels upon Pst (avrRps4) infections. Our findings suggest that AvrRps4 targets BTS to facilitate iron accumulation and BTS contributes to RPS4/EDS1-mediated immune responses.

scholarly journals Renal Iron Metabolism: Transferrin Iron Delivery and the Role of Iron Regulatory Proteins

2007 ◽  
Vol 18 (2) ◽  
pp. 401-406 ◽  
Author(s):  
Deliang Zhang ◽  
Esther Meyron-Holtz ◽  
Tracey A. Rouault
Keyword(s):  
Iron Metabolism ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Iron Delivery

Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients

2017 ◽  
Vol 138 (4) ◽  
pp. 183-193 ◽  
Author(s):  
Sintayehu Ambachew ◽  
Belete Biadgo
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Diabetic Patients ◽  
Hepatitis C Infection ◽  
Body Iron

The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin. However, inappropriate production of hepcidin has been shown to play a role in the pathogenesis of type 2 diabetes mellitus and its complications, based on the regulation and expression in iron-abundant cells. Underexpression of hepcidin results in body iron overload, which triggers the production of reactive oxygen species simultaneously thought to play a major role in diabetes pathogenesis mediated both by β-cell failure and insulin resistance. Increased hepcidin expression results in increased intracellular sequestration of iron, and is associated with the complications of type 2 diabetes. Besides, hepcidin concentrations have been linked to inflammatory cytokines, matriptase 2, and chronic hepatitis C infection, which have in turn been reported to be associated with diabetes by several approaches. Either hepcidin-targeted therapy alone or as adjunctive therapy with phlebotomy, iron chelators, or dietary iron restriction may be able to alter iron parameters in diabetic patients. Therefore, measuring hepcidin may improve differential diagnosis and the monitoring of disorders of iron metabolism.

Dysfunction of Iron Metabolism and Iron-Regulatory Proteins in the Rat Hippocampus After Heat Stroke

Shock ◽  
2019 ◽  
Vol 51 (6) ◽  
pp. 780-786 ◽  
Author(s):  
Jing Liu ◽  
Mingsheng Wan ◽  
Yun Zhang ◽  
Shu Zhang ◽  
Hongying Zhang ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Heat Stroke ◽  
Rat Hippocampus ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins

scholarly journals A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 85 ◽  
Author(s):  
Andronicos Yiannikourides ◽  
Gladys Latunde-Dada
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Cellular Proliferation ◽  
Peptide Hormone ◽  
Short Review ◽  
Reticuloendothelial System ◽  
Cellular Level ◽  
Feedback Mechanism ◽  
The Body ◽  
Iron Regulatory Proteins

Iron is a vital trace element for humans, as it plays a crucial role in oxygen transport, oxidative metabolism, cellular proliferation, and many catalytic reactions. To be beneficial, the amount of iron in the human body needs to be maintained within the ideal range. Iron metabolism is one of the most complex processes involving many organs and tissues, the interaction of which is critical for iron homeostasis. No active mechanism for iron excretion exists. Therefore, the amount of iron absorbed by the intestine is tightly controlled to balance the daily losses. The bone marrow is the prime iron consumer in the body, being the site for erythropoiesis, while the reticuloendothelial system is responsible for iron recycling through erythrocyte phagocytosis. The liver has important synthetic, storing, and regulatory functions in iron homeostasis. Among the numerous proteins involved in iron metabolism, hepcidin is a liver-derived peptide hormone, which is the master regulator of iron metabolism. This hormone acts in many target tissues and regulates systemic iron levels through a negative feedback mechanism. Hepcidin synthesis is controlled by several factors such as iron levels, anaemia, infection, inflammation, and erythropoietic activity. In addition to systemic control, iron balance mechanisms also exist at the cellular level and include the interaction between iron-regulatory proteins and iron-responsive elements. Genetic and acquired diseases of the tissues involved in iron metabolism cause a dysregulation of the iron cycle. Consequently, iron deficiency or excess can result, both of which have detrimental effects on the organism.

Multiple Causes of Iron Overload In Tissues, Cells and Subcellular Compartments

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Tracey Rouault
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract SCI-27 Iron metabolism is regulated in mammals to assure that adequate iron is delivered to the hematopoietic system to support erythropoiesis. In systemic iron metabolism, regulation of both iron uptake from the diet and release from erythrophagocytosing macrophages is coordinated by action of the peptide hormone, hepcidin, which inhibits activity of the iron exporter, ferroportin. In general, high expression of hepcidin diminishes duodenal iron uptake and reduces macrophage iron release, a combination observed in the anemia of chronic disease. Low expression of hepcidin, which is synthesized by hepatocytes and influenced by transferrin receptor 2, HFE, hemojuvelin and bone morphogenetic receptors, facilitates iron uptake. Mutations affecting genes in the hepcidin pathway cause hemochromatosis, characterized by systemic iron overload that affects mainly hepatocytes and cardiac myocytes, but spares the CNS. In contrast, there are several degenerative diseases of the CNS in which neuronal iron overload is prominent and may play a causal role. The underlying pathophysiologies of neuronal brain iron accumulation syndromes remain unclear, even though several causal genes have been identified, including pantothenate kinase 2 and aceruloplasminemia. In some cases, increased iron may be inaccessible, and cells may suffer from functional iron insufficiency, as we propose for animals that lack iron regulatory protein 2. It is also possible that errors in subcellular iron metabolism can lead to mitochondrial iron overload and concomitant cytosolic iron deficiency, a combination observed in Friedreich ataxia, ISCU myopathy, and the sideroblastic anemia caused by glutaredoxin 5 deficiency. In each of these diseases, mitochondrial iron-sulfur cluster assembly is impaired, and it appears that normal regulation of mitochondrial iron homeostasis depends on intact iron-sulfur cluster assembly. Finally, in heme oxygenase 1 deficient animals, macrophages in the spleen and liver die upon erythrophagocytosis, and failure to normally metabolize heme leads to shift of heme iron to proximal tubules and macrophages of the kidney. Thus, treatment of “iron overload” must depend on the underlying causes, and removal of iron is appropriate in hemochromatosis, but more specific forms of therapy are needed for other forms of iron overload. 1. Ye, H. & Rouault, T. A. (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 49, 4945–4956. 2. Zhang, A. S. & Enns, C. A. (2009). Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program 207–214. 3. Ye, H., Jeong, S. Y., Ghosh, M. C., Kovtunovych, G., Silvestri, L., Ortillo, D., Uchida, N., Tisdale, J., Camaschella, C. & Rouault, T. A. (2010). Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749–1761. 4. Ghosh, M. C., Tong, W. H., Zhang, D., Ollivierre-Wilson, H., Singh, A., Krishna, M. C., Mitchell, J. B. & Rouault, T. A. (2008). Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105, 12028–12033. 5. Crooks, D. R., Ghosh, M. C., Haller, R. G., Tong, W. H. & Rouault, T. A. (2010). Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869. Disclosures: No relevant conflicts of interest to declare.

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