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Alterations in Iron Metabolism and Erythropoiesis Related to Specific Metabolic...
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Alterations in Iron Metabolism and Erythropoiesis Related to Specific Metabolic Disorders

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 13923

Special Issue Editor

Dr. Zoubida Karim

E-Mail Website
Guest Editor
Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291-CNRS UMR5051-Université Toulouse III, 31024 Toulouse CEDEX 3, France
Interests: iron metabolism and related disorders; heme biosynthesis

Special Issue Information

Dear Colleagues,

In the body, heme and iron are essential for several biologic functions and metabolic reactions (oxygen binding by hemoglobin, myoglobin, oxygen metabolism by oxidases, peroxidases, catalases, and hydroxylases, and electron transfer by cytochromes). Because, iron is inserted in the center of the heme prosthetic group, iron and heme metabolisms are closely related and their associated disorders are frequently linked to the generation of abnormal metabolites (heme precursors) and/or oxidative stress (heme and iron overload). Heme biosynthesis is ubiquitous but rapid rates occurs in liver and erythroid cells where large amounts of heme are needed for mitochondrial cytochromes (~5%) and hemoglobin (~80%), respectively. Porphyrias is the specific metabolic diseases resulting in  alteration of erythroid and hepatic heme synthesis. However, heme balance may be disturbed indirectly by dyserythropoiesis including Diamond-Blackfan and sideroblastic anemias. Iron metabolism is regulated at the cellular and systemic level. Hemochromatosis (genetic or secondary) are the most known diseases related to iron balance disturbance. However, recent exploration of molecular mechanisms and cellular pathologies have shown that several metabolic diseases are associated with an accumulation of iron in specific tissues, including the brain, spleen and liver.

The aim of this Issue is to get an overview on the crosstalk between metabolic pathologies and heme and iron disorders. We focus on porpyhyrias, metabolic syndrome, lysosomal storage disorders (Gaucher  disease and symphilipo syndrome), Diamond-Blackfan anemia and iron loading anaemias. We also aim to highligh new methods allowing the detection of links between metabolic pathologies and iron and heme abnomalies.

Dr. Zoubida Karim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Iron metabolism
  • Heme biosynthesis
  • porphyrias
  • metabolic diseases
  • dyserythropoiesis
  • lysosomal disorders
  • porpyhyrias
  • lysosomal storage disorders
  • Iron loading anaemias

Published Papers (4 papers)

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Research

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11 pages, 4457 KiB  
Article
Crosstalk between Acidosis and Iron Metabolism: Data from In Vivo Studies
by Raêd Daher, Nicolas Ducrot, Thibaud Lefebvre, Sofia Zineeddine, Jérome Ausseil, Hervé Puy and Zoubida Karim
Metabolites 2022, 12(2), 89; https://doi.org/10.3390/metabo12020089 - 18 Jan 2022
Cited by 2 | Viewed by 2071
Abstract
Iron absorption requires an acidic environment that is generated by the activity of the proton pump gastric H(+)/K(+)ATPase (ATP4), expressed in gastric parietal cells. However, hepcidin, the iron regulatory peptide that inhibits iron absorption, unexpectedly upregulates ATP4 and increases gastric acidity. Thus, a [...] Read more.
Iron absorption requires an acidic environment that is generated by the activity of the proton pump gastric H(+)/K(+)ATPase (ATP4), expressed in gastric parietal cells. However, hepcidin, the iron regulatory peptide that inhibits iron absorption, unexpectedly upregulates ATP4 and increases gastric acidity. Thus, a concept of link between acidosis and alterations in iron metabolism, needs to be explored. We investigated this aspect in-vivo using experimental models of NH4Cl-induced acidosis and of an iron-rich diet. Under acidosis, gastric ATP4 was augmented. Serum hepcidin was induced and its mRNA level was increased in the liver but not in the stomach, a tissue where hepcidin is also expressed. mRNA and protein levels of intestinal DMT1(Divalent Metal Transporter 1) and ferroportin were downregulated. Serum iron level and transferrin saturation remained unchanged, but serum ferritin was significantly increased. Under iron-rich diet, the protein expression of ATP4A was increased and serum, hepatic and gastric hepcidin were all induced. Taken together, these results provide evidence of in-vivo relationship between iron metabolism and acidosis. For clinical importance, we speculate that metabolic acidosis may contribute in part to the pathologic elevation of serum hepcidin levels seen in patients with chronic kidney disease. The regulation of ATP4 by iron metabolism may also be of interest for patients with hemochromatosis. Full article
(This article belongs to the Special Issue Alterations in Iron Metabolism and Erythropoiesis Related to Specific Metabolic Disorders)
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Review

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29 pages, 7508 KiB  
Review
Iron Metabolism in the Disorders of Heme Biosynthesis
by Andrea Ricci, Giada Di Betto, Elisa Bergamini, Elena Buzzetti, Elena Corradini and Paolo Ventura
Metabolites 2022, 12(9), 819; https://doi.org/10.3390/metabo12090819 - 31 Aug 2022
Cited by 8 | Viewed by 2376
Abstract
Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme—the iron-chelated [...] Read more.
Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis. Full article
(This article belongs to the Special Issue Alterations in Iron Metabolism and Erythropoiesis Related to Specific Metabolic Disorders)
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18 pages, 823 KiB  
Review
Iron Metabolism in Normal and Pathological Pregnancies and Fetal Consequences
by Charles Mégier, Katell Peoc’h, Vincent Puy and Anne-Gaël Cordier
Metabolites 2022, 12(2), 129; https://doi.org/10.3390/metabo12020129 - 29 Jan 2022
Cited by 11 | Viewed by 5540
Abstract
Iron is required for energy production, DNA synthesis, and cell proliferation, mainly as a component of the prosthetic group in hemoproteins and as part of iron-sulfur clusters. Iron is also a critical component of hemoglobin and plays an important role in oxygen delivery. [...] Read more.
Iron is required for energy production, DNA synthesis, and cell proliferation, mainly as a component of the prosthetic group in hemoproteins and as part of iron-sulfur clusters. Iron is also a critical component of hemoglobin and plays an important role in oxygen delivery. Imbalances in iron metabolism negatively affect these vital functions. As the crucial barrier between the fetus and the mother, the placenta plays a pivotal role in iron metabolism during pregnancy. Iron deficiency affects 1.2 billion individuals worldwide. Pregnant women are at high risk of developing or worsening iron deficiency. On the contrary, in frequent hemoglobin diseases, such as sickle-cell disease and thalassemia, iron overload is observed. Both iron deficiency and iron overload can affect neonatal development. This review aims to provide an update on our current knowledge on iron and heme metabolism in normal and pathological pregnancies. The main molecular actors in human placental iron metabolism are described, focusing on the impact of iron deficiency and hemoglobin diseases on the placenta, together with normal metabolism. Then, we discuss data concerning iron metabolism in frequent pathological pregnancies to complete the picture, focusing on the most frequent diseases. Full article
(This article belongs to the Special Issue Alterations in Iron Metabolism and Erythropoiesis Related to Specific Metabolic Disorders)
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12 pages, 1163 KiB  
Review
Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay
by Antoine Poli, Caroline Schmitt, Boualem Moulouel, Arienne Mirmiran, Hervé Puy, Thibaud Lefèbvre and Laurent Gouya
Metabolites 2021, 11(12), 798; https://doi.org/10.3390/metabo11120798 - 23 Nov 2021
Cited by 13 | Viewed by 3299
Abstract
Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme [...] Read more.
Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of ALAS2 mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria. Full article
(This article belongs to the Special Issue Alterations in Iron Metabolism and Erythropoiesis Related to Specific Metabolic Disorders)
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