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Special Issue "Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 June 2020.

Special Issue Editors

Prof. Dr. Joannes J.M. Marx
Website
Guest Editor
University Medical Center Utrecht, Utrecht, Netherlands
Prof. Greg Anderson
Website
Guest Editor
Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road Brisbane, Queensland 4029, Australia
Interests: biology of iron; iron-related diseases; hemochromatosis; iron deficiency; biomedical applications of nanotechnology

Special Issue Information

Dear Colleague,

Iron is not only a crucial element for oxygen delivery in almost all living organisms, but also for the formation of toxic oxygen radicals that can lead to tissue damage if not controlled. Molecular advances in our understanding of iron homeostasis over the last 20 years have revolutionized how we think about body iron intake, distribution, utilization, and storage. Many new iron-related molecules have been described, our knowledge of how iron metabolism is regulated at both the cellular and systemic levels has expanded enormously, and we now have a far greater appreciation of the diversity of iron biology in different tissues. Defining the molecular underpinnings of iron-related diseases has gone hand in hand with these molecular advances, and the new knowledge we have gained about iron has led to the recognition that the metal plays critical roles in a broad range of pathophysiological processes. Results of earlier quantitative studies of iron absorption, ferrokinetics, utilization, and storage of iron, obtained with tracer techniques using radioisotopes can also now be reinterpreted in the light of our new knowledge. Despite these many new insights into iron metabolism, the story is far from complete, and the field of iron biology has never been more dynamic that it is today.

The editors of this Special Issue welcome original articles and reviews on pathophysiological and molecular aspects of iron metabolism.

Prof. Dr. Joannes J.M. Marx
Prof. Greg Anderson
Guest Editors

Manuscript Submission Information

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Keywords

  • iron uptake
  • iron absorption
  • iron metabolism
  • inflammation
  • host defence

Published Papers (3 papers)

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Research

Open AccessArticle
Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration
Int. J. Mol. Sci. 2020, 21(10), 3664; https://doi.org/10.3390/ijms21103664 - 22 May 2020
Abstract
Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme [...] Read more.
Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease. Full article
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Open AccessArticle
Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis
Int. J. Mol. Sci. 2020, 21(7), 2374; https://doi.org/10.3390/ijms21072374 - 30 Mar 2020
Abstract
Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) [...] Read more.
Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease. Full article
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Open AccessArticle
Liver Iron Retention Estimated from Utilization of Oral and Intravenous Radioiron in Various Anemias and Hemochromatosis in Humans
Int. J. Mol. Sci. 2020, 21(3), 1077; https://doi.org/10.3390/ijms21031077 - 06 Feb 2020
Abstract
Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of 59Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron [...] Read more.
Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of 59Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron uptake after oral and intravenous 59Fe administration. We present data from patients with iron deficiency (ID; N = 47), hereditary hemochromatosis (HH; N = 121) and non-transfusion-dependent hereditary anemia (HA; N = 40). Mean mucosal iron uptake and mucosal iron transfer (±SD) were elevated in patients with HH (59 ± 18%, 80 ± 15% respectively), HA (65 ± 17%, 74 ± 18%) and ID (84 ± 14%, 94 ± 6%) compared to healthy controls (43 ± 19%, 64 ± 18%) (p < 0.05) resulting in increased iron retention after 14 days compared to healthy controls in all groups (p < 0.01). The fraction of retained iron utilized for red cell production was 0.37 ± 0.17 in untreated HA, 0.55 ± 0.20 in untreated HH and 0.99 ± 0.22 in ID (p < 0.01). Interestingly, compared to red blood cell iron utilization after oral iron administration, red blood cell iron utilization was higher after injection of transferrin-bound iron in HA and HH. Liver iron retention was considerably higher in HH and HA compared to ID. We hypothesize that albumin serves as a scavenger of absorbed Fe(II) for delivering albumin-bound Fe(III) to hepatocytes. Full article
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