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Genetic Regulation in Iron Homeostasis
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Genetic Regulation in Iron Homeostasis

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 June 2021) | Viewed by 22003

Special Issue Editor

Prof. Dr. Paweł Lipiński

E-Mail Website
Guest Editor
Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Jastrzębiec, 05-552 Magdalenka, Poland
Interests: molecular regulation; genetically modified animals; iron metabolism; copper metabolism; heme/nonheme iron

Special Issue Information

Dear Colleagues,

Iron is an essential cofactor for biological processes, since it participates in multiple enzymatic reactions as a part of iron–sulfur clusters, heme prosthetic groups, and other iron-containing centers, which makes it indispensable for all living organisms, except for a few bacterial species. However, the propensity of iron to generate reactive free radicals through the Fenton reaction makes this biometal a doubled-edged sword in a biological oxygen environment. Since there is no natural pathway for excreting excess iron from the organism, systemic iron homeostasis must be very tightly controlled in order to ensure coordinated iron absorption by enterocytes, its recycling by macrophages of the reticuloendothelial system, and correct redistribution to its site of utilization or storage. Furthermore, it seems increasingly evident now that tissue- and cell-specific iron regulatory networks play a crucial role in maintaining both local and organismal iron homeostasis.

Over the past twenty years, our understanding of iron metabolism in eucaryotes has increased exponentially. Genetic studies of patients with inherited iron homeostasis disorders and the analysis of genetically modified laboratory animals have contributed to the identification of several new genes important in cellular and systemic iron homeostasis, and their roles have been intensively investigated. Nevertheless, despite such progress in the field of iron biology, our view of cellular and systemic iron metabolism is far from exhausted. As a Guest Editor, I strongly encourage researchers from the “iron community” to submit original articles and reviews to this Special Issue of Genes.

Prof. Dr. Paweł Lipiński
Guest Editor

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Keywords

  • Iron homeostasis
  • Iron regulation
  • Iron-related genes
  • Iron deficiency/overload genetic models

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Published Papers (6 papers)

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Research

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14 pages, 2295 KiB  
Article
The Role of the Trabecular Bone Score in the Assessment of Osteoarticular Disorders in Patients with HFE-Hemochromatosis: A Single-Center Study from Poland
by Katarzyna Banaszkiewicz, Katarzyna Sikorska, Damian Panas and Krzysztof Sworczak
Genes 2021, 12(9), 1304; https://doi.org/10.3390/genes12091304 - 25 Aug 2021
Cited by 2 | Viewed by 2534
Abstract
Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of HFE gene mutations, which are associated with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite [...] Read more.
Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of HFE gene mutations, which are associated with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite a properly conducted treatment with phlebotomies. In this study, selected parameters of calcium and phosphate metabolism were analyzed in combination with the assessment of bone mineral density (BMD) disorders in patients from northern Poland with clinically overt HFE-HH. BMD was determined by a dual-energy X-ray absorptiometry (DXA) test with the use of the trabecular bone score (TBS) function. The study included 29 HH patients (mean age = 53.14 years) who were compared with 20 healthy volunteers. A significantly lower TBS parameter and serum 25-OH-D3 concentration, a higher concentration of intact parathormone and more a frequent occurrence of joint pain were found in HH patients compared with the control group. In HH patients, the diagnosis of liver cirrhosis was associated with lower serum 25-OH-D3 and osteocalcin concentrations. In HH, DXA with the TBS option is a valuable tool in the early assessment of the bone microarchitecture and fracture risk. A supplementation of vitamin D, monitoring its concentration, should be considered especially in HH patients with liver damage and liver cirrhosis. Full article
(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)
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12 pages, 4703 KiB  
Article
HFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary Hemochromatosis
by Miriam Sandnes, Marta Vorland, Rune J. Ulvik and Håkon Reikvam
Genes 2021, 12(8), 1162; https://doi.org/10.3390/genes12081162 - 28 Jul 2021
Cited by 6 | Viewed by 2961
Abstract
HFE hemochromatosis is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Overt disease is mainly associated with homozygosity for the C282Y variant, although the H63D variant in compound heterozygosity with C282Y (C282Y/H63D) contributes to disease [...] Read more.
HFE hemochromatosis is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Overt disease is mainly associated with homozygosity for the C282Y variant, although the H63D variant in compound heterozygosity with C282Y (C282Y/H63D) contributes to disease manifestation. In this observational study, we describe the association between biochemical findings, age, gender and HFE genotype in patients referred from general practice to a tertiary care referral center for diagnostic workup based on suspected hemochromatosis due to persistent hyperferritinemia and HFE variants. C282Y and H63D homozygosity were, respectively, the most and least prevalent genotypes and we found a considerable variation in transferrin saturation and ferritin levels independent of HFE genotype, which may indeed represent a diagnostic challenge in general practice. While our results confirm C282Y homozygosity as the major cause of iron accumulation, non-C282Y homozygotes also displayed mild to moderate hyperferritinemia with median ferritin levels at 500–700 µg/L, well above the reference cut-off. Such findings have traditionally been ignored in the clinic, and initiation of iron depletion has largely been restricted to C282Y homozygotes. Nevertheless, superfluous iron can aggravate pathogenesis in combination with other diseases and risk factors, such as inflammation, cancer and hepatopathy, and this possibility should not be neglected by clinicians. Full article
(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)
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13 pages, 1685 KiB  
Article
Expression of a Truncated Yeast Ccc1 Vacuolar Transporter Increases the Accumulation of Endogenous Iron
by Raquel Sorribes-Dauden, María Teresa Martínez-Pastor and Sergi Puig
Genes 2021, 12(8), 1120; https://doi.org/10.3390/genes12081120 - 23 Jul 2021
Cited by 3 | Viewed by 2640
Abstract
Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in multiple metabolic processes. Iron bioavailability is highly restricted due to the low solubility of its oxidized form, frequently leading to iron deficiency anemia. The baker’s yeast [...] Read more.
Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in multiple metabolic processes. Iron bioavailability is highly restricted due to the low solubility of its oxidized form, frequently leading to iron deficiency anemia. The baker’s yeast Saccharomyces cerevisiae is used as a model organism for iron homeostasis studies, but also as a food supplement and fermentative microorganism in the food industry. Yeast cells use the vacuolar Ccc1 transporter to detoxify and store excess iron in the vacuoles. Here, we modulate CCC1 expression and properties to increase iron extraction from the environment. We show that constitutive expression of full-length CCC1 is toxic, whereas deletion of its cytosolic amino-terminal (Nt) domain (NtΔCCC1) rescues this phenotype. Toxicity is exacerbated in cells lacking AFT1 transcription factor. Further characterization of NtΔCcc1 protein suggests that it is a partially functional protein. Western blot analyses indicate that deletion of Ccc1 Nt domain does not significantly alter GFP-Ccc1 protein stability. A functional full-length GFP-Ccc1 protein localized to particular regions of the vacuolar membrane, whereas GFP-NtΔCcc1 protein was evenly distributed throughout this endogenous membrane. Interestingly, expression of NtΔCCC1 increased the accumulation of endogenous iron in cells cultivated under iron-sufficient conditions, a strategy that could be used to extract iron from media that are not rich in iron. Full article
(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)
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Review

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13 pages, 315 KiB  
Review
Role of Iron Metabolism-Related Genes in Prenatal Development: Insights from Mouse Transgenic Models
by Zuzanna Kopeć, Rafał R. Starzyński, Aneta Jończy, Rafał Mazgaj and Paweł Lipiński
Genes 2021, 12(9), 1382; https://doi.org/10.3390/genes12091382 - 2 Sep 2021
Cited by 6 | Viewed by 2854
Abstract
Iron is an essential nutrient during all stages of mammalian development. Studies carried out over the last 20 years have provided important insights into cellular and systemic iron metabolism in adult organisms and led to the deciphering of many molecular details of its [...] Read more.
Iron is an essential nutrient during all stages of mammalian development. Studies carried out over the last 20 years have provided important insights into cellular and systemic iron metabolism in adult organisms and led to the deciphering of many molecular details of its regulation. However, our knowledge of iron handling in prenatal development has remained remarkably under-appreciated, even though it is critical for the health of both the embryo/fetus and its mother, and has a far-reaching impact in postnatal life. Prenatal development requires a continuous, albeit quantitatively matched with the stage of development, supply of iron to support rapid cell division during embryogenesis in order to meet iron needs for erythropoiesis and to build up hepatic iron stores, (which are the major source of this microelement for the neonate). Here, we provide a concise overview of current knowledge of the role of iron metabolism-related genes in the maintenance of iron homeostasis in pre- and post-implantation development based on studies on transgenic (mainly knock-out) mouse models. Most studies on mice with globally deleted genes do not conclude whether underlying in utero iron disorders or lethality is due to defective placental iron transport or iron misregulation in the embryo/fetus proper (or due to both). Therefore, there is a need of animal models with tissue specific targeted deletion of genes to advance the understanding of prenatal iron metabolism. Full article
(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)
22 pages, 2194 KiB  
Review
The Multiple Facets of Iron Recycling
by Patryk Slusarczyk and Katarzyna Mleczko-Sanecka
Genes 2021, 12(9), 1364; https://doi.org/10.3390/genes12091364 - 30 Aug 2021
Cited by 24 | Viewed by 7411
Abstract
The production of around 2.5 million red blood cells (RBCs) per second in erythropoiesis is one of the most intense activities in the body. It continuously consumes large amounts of iron, approximately 80% of which is recycled from aged erythrocytes. Therefore, similar to [...] Read more.
The production of around 2.5 million red blood cells (RBCs) per second in erythropoiesis is one of the most intense activities in the body. It continuously consumes large amounts of iron, approximately 80% of which is recycled from aged erythrocytes. Therefore, similar to the “making”, the “breaking” of red blood cells is also very rapid and represents one of the key processes in mammalian physiology. Under steady-state conditions, this important task is accomplished by specialized macrophages, mostly liver Kupffer cells (KCs) and splenic red pulp macrophages (RPMs). It relies to a large extent on the engulfment of red blood cells via so-called erythrophagocytosis. Surprisingly, we still understand little about the mechanistic details of the removal and processing of red blood cells by these specialized macrophages. We have only started to uncover the signaling pathways that imprint their identity, control their functions and enable their plasticity. Recent findings also identify other myeloid cell types capable of red blood cell removal and establish reciprocal cross-talk between the intensity of erythrophagocytosis and other cellular activities. Here, we aimed to review the multiple and emerging facets of iron recycling to illustrate how this exciting field of study is currently expanding. Full article
(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)
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21 pages, 1397 KiB  
Review
Complex Interactions in Regulation of Haematopoiesis—An Unexplored Iron Mine
by Ranita De, Kulkarni Uday Prakash and Eunice S. Edison
Genes 2021, 12(8), 1270; https://doi.org/10.3390/genes12081270 - 20 Aug 2021
Cited by 5 | Viewed by 2584
Abstract
Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable [...] Read more.
Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable proteins and enzymes. It plays a pivotal role in haematopoiesis and affects the development and differentiation of different haematopoietic lineages, apart from its obvious necessity in erythropoiesis. A large amount of iron stores in humans is diverted towards the latter process, as iron is an indispensable component of haemoglobin. This review summarises the important players of iron metabolism and homeostasis that have been discovered in recent years and highlights the overall significance of iron in haematopoiesis. Its role in maintenance of haematopoietic stem cells, influence on differentiation of varied haematopoietic lineages and consequences of iron deficiency/overloading on development and maturation of different groups of haematopoietic cells have been discussed. Full article
(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)
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