Translational regulation of iron metabolism pdf

Translational regulation of mammalian ferritin synthesis in response to iron and the apparent links between iron and citrate metabolism through a single molecule with dual function are described. The ironresponsive element is the single element responsible for irondependent translational regulation of ferritin biosynthesis. Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. In contrast to translational regulation, hepcidin regulates ferroportin. We have shown that, in human k562 and mel cells, epo activates presumably irp1, the central regulatory protein for orchestrating cellular iron metabolism via posttranscriptional and translational modulation of the expression of the proteins involved in cellular iron uptake, storage, and consumption. Jan 14, 2020 global translational repression induced by iron deficiency in yeast depends on the gcn2eif2. The regulation of iron metabolism involves the interaction of a number of specific proteins as well as the interplay between iron absorption, recycling, and iron loss. The molecular biology of human iron metabolism oxford academic. Because iron is both indispensable and potentially toxic, virtually all cells and organisms regulate uptake and utilization of iron. Translational regulation archives of disease in childhood. Identification of the ironresponsive element for the.

Translational regulation of mammalian ferritin synthesis in response to iron and the apparent links between iron and citrate metabolism through a. In molecular biology, the iron response element or iron responsive element ire is a short conserved stemloop which is bound by iron response proteins irps, also named irebp or irbp. Note that much of the regulation of iron metabolism occurs via the regulation of translation and not transcription. Tfr are the major proteins involved in the regulation of iron homeostasis. Cell growth and erythropoiesis are most critically affected by iron deficiency, while iron overload predominantly causes hepatic and degenerative disease. Regulation of the iron homeostatic hormone hepcidin. Evidence for function as the binding site for a translational repressor. Ferritin synthesis is translationally regulated by iron.

Caughman sw, hentze mw, rouault ta, harford jb, klausner rd. Translational control in copper and iron metabolism. Of all of these mechanisms, post translational regulation by hepcidin is the ultimate and decisive step in controlling iron homeostasis. Because iron loss from the body is not regulated and can only be achieved through desquamation or bleeding, the critical focus of systemic iron regulation is on iron influx into the circulation that involves iron absorption from the enterocytes and iron release from hepatocytes and macrophages. We demonstrate that induction of nos in macrophage and non.

Regulation of metabolism page 4 regulation of metabolism approximate lecture schedule, fall 2009 dates will be updated to 2011 podcasts available here need quicktime to view day of date week tentative topic reading. Pdf translational regulation via ironresponsive elements. These irecontaining mrnas are regulated by binding of a cytoplasmic protein, iron regulatory protein irp1. An overview of molecular basis of iron metabolism regulation. The normal iron circuit includes the uptake of iron from transferrin by developing erythroblasts, the incorporation of iron into heme, red blood cell rbc production, rbc survival, and rbc senescence in the spleen with return of iron to the bone marrow via transferrin.

Translational control mechanisms in metabolic regulation. Cell metabolism article a ferroportin transcript that lacks an iron responsive element enables duodenal and erythroid precursor cells to evade translational repression deliang zhang,1 robert m. It includes the iron intake upto the storage and recycling. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. These forms are not attributed to mutations in the hfe gene but rather to mutations in genes involved in the transport, storage, and regulation of iron. Ferroportin and iron regulation in breast cancer progression. The regulation of hamp expression by iron levels is a process through which the human body avoids both the toxic outcomes of iron overload and the negative physiological consequences of its deficiency. Translational effects mediated by iron, heme, and cytokines. Mar 15, 2011 until the mid1980s, the bioiron field was restricted to the study of tf, tfr1 and ferritin.

Decreased iron concentration prevents protein oxidation by hydroxyl radicals generated in the fenton reaction. Translational regulation of mrnas with distinct ire sequences. Posttranscriptional regulation of iron metabolism springerlink. The mechanism for translational regulation of ferritin synthesis involves the 5untranslated region 5utr of ferritin mrnas, where a sequence of 28 nt is almost perfectly preserved in h and lferritin mrnas from various animal species 1,3,5,6. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. Translational regulation of mrnas with distinct ire sequences by iron regulatory proteins 1 and 2. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking. Molecular biology of human iron metabolism laboratory. Role of rna secondary structure of the ironresponsive. Cells are able to regulate themselves the expression of the iron metabolism related genes through different posttranscriptional mechanisms, such as the alternative splicing, micrornas, the irpire system and the proteolytic cleavage. A cisacting element that is both necessary and sufficient for this translational regulation is present within the 5 nontranslated leader region of the human ferritin hchain messenger rna. Translational regulation an overview sciencedirect topics. Iron metabolism disorders most common form of anemia symptom of pathologic process primary manifestation is hematologic treatment requires.

A tight regulation of iron balance is essential to avoid both iron deficiency and overload. In this video we have discussed the physiology of iron metabolism in humans. Translational regulation via ironresponsive elements by the. 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. Regulation of iron metabolism is a fundamental process with profound medical implications. May 15, 2003 cytokinemediated regulation of iron transport in human monocytic cells susanne ludwiczek 1 from the department of internal medicine, university hospital, innsbruck, austria. We describe a novel role of no as a signaling molecule in post. The biosynthesis of the intracellular iron storage protein ferritin is translationally regulated by iron. Review article aconitase posttranslational modification as a. Novel mechanism for translational control in regulation of. Iron uptake in the brain is mediated by the expression of tfr on the luminal endothelial surface in the bloodbrain barrier. The role played by the analysis of inherited disorders of iron metabolism in helping us to understand iron transport and its regulation cannot be underestimated, and some of the key defects investigated are summarized in table 1. At the molecular level, binding of hepcidin to fpn1 causes receptor ubiquitination, internalization, and subsequent lysosomal degradation in vitro.

Ferroportin is the only known mechanism for export of intracellular nonhemeassociated iron. The regulation of many iron metabolism proteins, including ferritin and transferrin receptor depends upon binding of iron regulatory proteins to rna stemloops found within the transcripts that encode these proteins. Thus, iron homeostasis also involves a proteolytic pathway that couples with irebp2dependent translational regulation in cells. The iron responsive element is the single element responsible for iron dependent translational regulation of ferritin biosynthesis. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular. Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. The ire is found in utrs untranslated regions of various mrnas whose products are involved in iron metabolism. Several proteins located at the surface of hepatocytes are considered to be iron sensors. Feb 05, 2017 medicinebiochemistry lesson on iron absorption, transport in the blood, metabolism and regulation of iron uptake in the body. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Global translational repression induced by iron deficiency in. Translational control mechanisms are also involved in both iron and copper metabolism. An overview of molecular basis of iron metabolism regulation and. However, in the case of ferritin mrna, irpire interaction inhibits its translation and.

Replacement therapy correction of underlying cause if possiblecorrection of underlying cause if possible iron excess more dangerous than iron deficiency. Circadian regulation of behaviors, hormones, physiology, metabolism, and energetics. Iron absorption, transport, metabolism and regulation. Regulation of cellular iron metabolism pubmed central pmc. One of the key components of the iron uptake and storage pathway is ferritin, a protein that sequesters iron in a nontoxic form. Disrupted iron regulation in the brain and periphery in. This allows for rapid and precise changes in the absorption of iron from the diet. Iron is both necessary to the body and potentially toxic. This sequence, which has been named the iron responsive element. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of. The subsequent discovery of the ireirp system prepared the way for understanding the coordinate regulation of cellular iron metabolism. Novel mechanism for translational control in regulation of ferritin synthesis by iron j zahringer, b s baliga, h n munro proceedings of the national academy of sciences mar 1976, 73 3 857861.

Until the mid1980s, the bioiron field was restricted to the study of tf, tfr1 and ferritin. Supplemental figures and supplemental tables 12 read more. This is advantageous because the abundance of a subunit is generally a poor indicator of its rate of synthesis. Sep 10, 2018 in this video we have discussed the physiology of iron metabolism in humans. Tight regulation of iron metabolism is imperative for its homeostasis. Living with iron childrens hospital oakland research institute. Translational regulation has been revealed by changes in the synthesis rates of photosynthesis complex subunits that occur in the absence of corresponding alterations of mrna abundance. Dysregulation of iron metabolism in alzheimers disease. Cytokinemediated regulation of iron transport in human. Recent advances in the knowledge of iron metabolism underscore its complex relationship to overall cell metabolism. Regulation of cellular iron metabolism biochemical journal. The best known example of translational regulation by molecules binding to the mrna is the intracellular control of iron concentrations. Regulation of cellular iron metabolism by erythropoietin. Translational regulation via ironresponsive elements by nitric oxidenosynthase pathway article pdf available in the embo journal 129.