Current understanding of iron homeostasis Anderson, Gregory J; Frazer, David M
The American journal of clinical nutrition,
12/2017, Letnik:
106, Številka:
suppl_6
Journal Article
Recenzirano
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Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron concentrations within the optimal ...physiologic range. In the diet, iron is either sequestered within heme or in various nonheme forms. Although the absorption of heme iron is poorly understood, nonheme iron is transported across the apical membrane of the intestinal enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1). Newly absorbed iron binds to plasma transferrin and is distributed around the body to sites of utilization with the erythroid marrow having particularly high iron requirements. Iron-loaded transferrin binds to transferrin receptor 1 on the surface of most body cells, and after endocytosis of the complex, iron enters the cytoplasm via DMT1 in the endosomal membrane. This iron can be used for metabolic functions, stored within cytosolic ferritin, or exported from the cell via FPN1. Cellular iron concentrations are modulated by the iron regulatory proteins (IRPs) IRP1 and IRP2. At the whole-body level, dietary iron absorption and iron export from the tissues into the plasma are regulated by the liver-derived peptide hepcidin. When tissue iron demands are high, hepcidin concentrations are low and vice versa. Too little or too much iron can have important clinical consequences. Most iron deficiency reflects an inadequate supply of iron in the diet, whereas iron excess is usually associated with hereditary disorders. These disorders include various forms of hemochromatosis, which are characterized by inadequate hepcidin production and, thus, increased dietary iron intake, and iron-loading anemias whereby both increased iron absorption and transfusion therapy contribute to the iron overload. Despite major recent advances, much remains to be learned about iron physiology and pathophysiology.
Iron is an essential element for almost all organisms, a cofactor playing a crucial role in a number of vital functions, including oxygen transport, DNA synthesis, and respiration. However, its ...ability to exchange electrons renders excess iron potentially toxic, since it is capable of catalyzing the formation of highly poisonous free radicals. As a consequence, iron homeostasis is tightly controlled by sophisticated mechanisms that have been partially elucidated. Because of its biological importance, numerous disorders have been recently linked to the deregulation of iron homeostasis, which include not only the typical disorders of iron overload and deficiency but also cancer and neurodegenerative diseases. This leads iron metabolism to become an interesting therapeutic target for novel pharmacological treatments against these diseases. Several therapies are currently under development for hematological disorders, while other are being considered for different pathologies. The therapeutic targeting under study includes the hepcidin/ferroportin axis for the regulation of systemic iron homeostasis, complex cytosolic machineries for the regulation of the intracellular iron status and its association with oxidative damage, and reagents exploiting proteins of iron metabolism such as ferritin and transferrin receptor. A promising potential target is a recently described form of programmed cell death named ferroptosis, in which the role of iron is essential but not completely clarified. This Special Issue has the aim to summarize the state-of-the-art, and the latest findings published in the iron field, as well as to elucidate future directions.
Iron is an essential element for almost all organisms, a cofactor playing a crucial role in a number of vital functions, including oxygen transport, DNA synthesis, and respiration. However, its ...ability to exchange electrons renders excess iron potentially toxic, since it is capable of catalyzing the formation of highly poisonous free radicals. As a consequence, iron homeostasis is tightly controlled by sophisticated mechanisms that have been partially elucidated. Because of its biological importance, numerous disorders have been recently linked to the deregulation of iron homeostasis, which include not only the typical disorders of iron overload and deficiency but also cancer and neurodegenerative diseases. This leads iron metabolism to become an interesting therapeutic target for novel pharmacological treatments against these diseases. Several therapies are currently under development for hematological disorders, while other are being considered for different pathologies. The therapeutic targeting under study includes the hepcidin/ferroportin axis for the regulation of systemic iron homeostasis, complex cytosolic machineries for the regulation of the intracellular iron status and its association with oxidative damage, and reagents exploiting proteins of iron metabolism such as ferritin and transferrin receptor. A promising potential target is a recently described form of programmed cell death named ferroptosis, in which the role of iron is essential but not completely clarified. This Special Issue has the aim to summarize the state-of-the-art, and the latest findings published in the iron field, as well as to elucidate future directions.
Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this ...minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins.
Iron Homeostasis in Health and Disease Gozzelino, Raffaella; Arosio, Paolo
International Journal of Molecular Sciences,
01/2016, Letnik:
17, Številka:
1
Journal Article, Book Review
Recenzirano
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Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and ...diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload.
Understanding the iron status in pregnant women in Europe provides a foundation for considering the role of iron screening and supplementation. However, available reports and studies have used ...different approaches that challenge the devising of overall summaries. Moreover, data on pregnant women are limited, and thus, data on women of reproductive age provide useful background information including baseline iron stores in pregnant women. This review considered data that are available from >15 European countries including national surveys and relevant clinical studies. In European women of reproductive age, median or geometric mean serum ferritin (SF) concentrations were estimated at 26–38 μg/L. Approximately 40–55% of this population had small or depleted iron stores (i.e., SF concentration ≤30 μg/L), and 45–60% of this population had apparently replete iron stores. The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) was 10–32% and 2–5%, respectively, depending on the cutoffs used. Approximately 20–35% of European women of reproductive age had sufficient iron stores (SF concentration >70 μg/L) to complete a pregnancy without supplementary iron. During pregnancy, European women in controlled supplementation trials who were not receiving iron supplements displayed increasing prevalences of ID and IDA during pregnancy, which peaked in the middle to late third trimester. Available evidence has suggested that, in gestational weeks 32–39, the median or geometric mean SF concentrations were 6–21 μg/L, and prevalences of ID and IDA were 28–85% and 21–35%, respectively. Women who were taking iron supplements had higher iron status and lower prevalences of ID and IDA, which were dependent on the dose of iron and compliance. The data suggest that, in Europe, the iron status of reproductive-aged women varies by region and worsens in pregnancy without iron supplementation.
Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection ...to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.
Iron deficiency in pregnancy Georgieff, Michael K.
American journal of obstetrics and gynecology,
10/2020, Letnik:
223, Številka:
4
Journal Article
Recenzirano
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Iron is essential for the function of all cells through its roles in oxygen delivery, electron transport, and enzymatic activity. Cells with high metabolic rates require more iron and are at greater ...risk for dysfunction during iron deficiency. Iron requirements during pregnancy increase dramatically, as the mother’s blood volume expands and the fetus grows and develops. Thus, pregnancy is a condition of impending or existing iron deficiency, which may be difficult to diagnose because of limitations to commonly used biomarkers such as hemoglobin and ferritin concentrations. Iron deficiency is associated with adverse pregnancy outcomes, including increased maternal illness, low birthweight, prematurity, and intrauterine growth restriction. The rapidly developing fetal brain is at particular risk of iron deficiency, which can occur because of maternal iron deficiency, hypertension, smoking, or glucose intolerance. Low maternal gestational iron intake is associated with autism, schizophrenia, and abnormal brain structure in the offspring. Newborns with iron deficiency have compromised recognition memory, slower speed of processing, and poorer bonding that persist despite postnatal iron repletion. Preclinical models of fetal iron deficiency confirm that expected iron-dependent processes such as monoamine neurotransmission, neuronal growth and differentiation, myelination, and gene expression are all compromised acutely and long term into adulthood. This review outlines strategies to diagnose and prevent iron deficiency in pregnancy. It describes the neurocognitive and mental health consequences of fetal iron deficiency. It emphasizes that fetal iron is a key nutrient that influences brain development and function across the lifespan.
Biomarkers of Nutrition for Development (BOND)—Iron Review Lynch, Sean; Pfeiffer, Christine M; Georgieff, Michael K ...
The Journal of nutrition,
June 2018, 2018-06-01, 2018-06-00, 20180601, Letnik:
148, Številka:
suppl_1
Journal Article
Recenzirano
Odprti dostop
This is the fifth in the series of reviews developed as part of the Biomarkers of Nutrition for Development (BOND) program. The BOND Iron Expert Panel (I-EP) reviewed the extant knowledge regarding ...iron biology, public health implications, and the relative usefulness of currently available biomarkers of iron status from deficiency to overload. Approaches to assessing intake, including bioavailability, are also covered. The report also covers technical and laboratory considerations for the use of available biomarkers of iron status, and concludes with a description of research priorities along with a brief discussion of new biomarkers with potential for use across the spectrum of activities related to the study of iron in human health. The I-EP concluded that current iron biomarkers are reliable for accurately assessing many aspects of iron nutrition. However, a clear distinction is made between the relative strengths of biomarkers to assess hematological consequences of iron deficiency versus other putative functional outcomes, particularly the relationship between maternal and fetal iron status during pregnancy, birth outcomes, and infant cognitive, motor and emotional development. The I-EP also highlighted the importance of considering the confounding effects of inflammation and infection on the interpretation of iron biomarker results, as well as the impact of life stage. Finally, alternative approaches to the evaluation of the risk for nutritional iron overload at the population level are presented, because the currently designated upper limits for the biomarker generally employed (serum ferritin) may not differentiate between true iron overload and the effects of subclinical inflammation.
Both iron deficiency (ID) and excess can lead to impaired health status. There is substantial evidence of a U-shaped curve between the risk of adverse birth outcomes and maternal hemoglobin ...concentrations during pregnancy; however, it is unclear whether those relations are attributable to conditions of low and high iron status or to other mechanisms. We summarized current evidence from human studies regarding the association between birth outcomes and maternal hemoglobin concentrations or iron status. We also reviewed effects of iron supplementation on birth outcomes among women at low risk of ID and the potential mechanisms for adverse effects of high iron status during pregnancy. Overall, we confirmed a U-shaped curve for the risk of adverse birth outcomes with maternal hemoglobin concentrations, but the relations differ by trimester. For low hemoglobin concentrations, the link with adverse outcomes is more evident when hemoglobin concentrations are measured in early pregnancy. These relations generally became weaker or nonexistent when hemoglobin concentrations are measured in the second or third trimesters. Associations between high hemoglobin concentration and adverse birth outcomes are evident in all 3 trimesters but evidence is mixed. There is less evidence for the associations between maternal iron status and adverse birth outcomes. Most studies used serum ferritin (SF) concentrations as the indicator of iron status, which makes the interpretation of results challenging because SF concentrations increase in response to inflammation or infection. The effect of iron supplementation during pregnancy may depend on initial iron status. There are several mechanisms through which high iron status during pregnancy may have adverse effects on birth outcomes, including oxidative stress, increased blood viscosity, and impaired systemic response to inflammation and infection. Research is needed to understand the biological processes that underlie the U-shaped curves seen in observational studies. Reevaluation of cutoffs for hemoglobin concentrations and indicators of iron status during pregnancy is also needed.
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