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Special Issue "Metal Metabolism in Animals"

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

Deadline for manuscript submissions: closed (29 February 2016).

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A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Reinhard Dallinger
E-Mail Website
Guest Editor
Institute of Zoology, University of Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria
Interests: environmental toxicology and ecotoxicology; molecular physiology; microevolution of metal sensitivity; evolution; biochemistry and gene regulation of metallothioneins; metal-specific pathways in animal physiology; metal detoxification; metal-related biological indicators and biomarkers
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Special Issue Information

Dear Colleagues,

Metal metabolism in animals has been in the spotlight for more than 100 years. Never before, however, has the opportunity to shed light on metal interactions and their implications been as promising as it is today. Several important insights and achievements may have contributed to this development. One important step has been the realization that intracellular concentrations and activities of metal ions are strictly controlled by the cell, with the consequence that intracellular free metal ion levels are regulated at very low concentrations. On the other hand, metal ions are dynamically involved in cellular processes through continuous beneficial, or detrimental, interaction with intracellular ligands, co-factors and metabolites. The improvement of analytical techniques has greatly assisted in the discovery of these insights. However, our understanding of metal interactions with biological systems has been most notably expanded by the sophistication of molecular biology tools and bioinformatics. One of the most promising developments is the new integrative approach of metallomics, which spans the entirety of metal interactions with living systems, including their environmental interdependencies.

In this light, study of metal interactions in animals and animal cells offer the exciting possibility of resolving many molecular, biochemical, physiological and environmental questions which remain open. The present issue aims at bringing together, under a metallomics perspective, important contributions to the field of metal metabolism in animals.

In particular, we welcome topics covering:

  • Regulation and control of metal ion concentrations in subcellular, cellular and tissue-specific compartments of animals, with special emphasis on the interaction of metals with extra and intracellular ligands, metabolites and co-factors;
  • Mechanisms of metal ion transport, sensing, storage and detoxification in animals, and biomolecules involved in these processes;
  • Role of metal ions in molecular signaling pathways within the animal cell, involving interactions with transcription factors and genes;
  • Shedding light on the functional aspects of metal metabolism in animals by applying genomic, proteomic and bioinformatic approaches;
  • Adverse and toxic effects of metal ions towards important cellular processes and pathways, from molecular to the organismic level;
  • Detrimental interactions of metal ions through the formation of reactive oxygen species in animal cells, and cellular strategies to overcome these effects;
  • Metal ion speciation and biological availability in the environment and implications for processes of metal uptake and balance within animal cells;
  • Trans-generational effects of metals, with emphasis on epigenetic mechanisms and their implications;
  • Any other topic focusing, in an integrative manner, on metal metabolism in animals, by addressing molecular and physiological aspects.

Prof. Dr. Reinhard Dallinger
Guest Editor

Manuscript Submission Information

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Keywords

  • Molecular Physiology
  • Bioaccumulation and Biotoxicity
  • Oxidative Stress and Reactive Oxygen Species
  • Metal Turnover, Metabolism and Regulation
  • Metal Transporter
  • Metal Sensing, Signaling and Reactions
  • Analytical Techniques
  • Metallochaperone, Metalloprotein, Metallothionein and the alike
  • Organometallics
  • Chelation, Chelator, Complexation, Complex Formation
  • Metal Detoxification, Sequestration and Compartmentalization
  • Functional Genomics and Proteomics
  • Transcriptional Regulation and Transcription Factors

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Published Papers (11 papers)

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Research

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Article
Deletion of Phytochelatin Synthase Modulates the Metal Accumulation Pattern of Cadmium Exposed C. elegans
Int. J. Mol. Sci. 2016, 17(2), 257; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020257 - 19 Feb 2016
Cited by 11 | Viewed by 2745
Abstract
Environmental metal pollution is a growing health risk to flora and fauna. It is therefore important to fully elucidate metal detoxification pathways. Phytochelatin synthase (PCS), an enzyme involved in the biosynthesis of phytochelatins (PCs), plays an important role in cadmium detoxification. The PCS [...] Read more.
Environmental metal pollution is a growing health risk to flora and fauna. It is therefore important to fully elucidate metal detoxification pathways. Phytochelatin synthase (PCS), an enzyme involved in the biosynthesis of phytochelatins (PCs), plays an important role in cadmium detoxification. The PCS and PCs are however not restricted to plants, but are also present in some lower metazoans. The model nematode Caenorhabditis elegans, for example, contains a fully functional phytochelatin synthase and phytochelatin pathway. By means of a transgenic nematode strain expressing a pcs-1 promoter-tagged GFP (pcs-1::GFP) and a pcs-1 specific qPCR assay, further evidence is presented that the expression of the C. elegans phytochelatin synthase gene (pcs-1) is transcriptionally non-responsive to a chronic (48 h) insult of high levels of zinc (500 μM) or acute (3 h) exposures to high levels of cadmium (300 μM). However, the accumulation of cadmium, but not zinc, is dependent on the pcs-1 status of the nematode. Synchrotron based X-ray fluorescence imaging uncovered that the cadmium body burden increased significantly in the pcs-1(tm1748) knockout allele. Taken together, this suggests that whilst the transcription of pcs-1 may not be mediated by an exposure zinc or cadmium, it is nevertheless an integral part of the cadmium detoxification pathway in C. elegans. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Article
Earthworm Lumbricus rubellus MT-2: Metal Binding and Protein Folding of a True Cadmium-MT
Int. J. Mol. Sci. 2016, 17(1), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010065 - 05 Jan 2016
Cited by 13 | Viewed by 4835
Abstract
Earthworms express, as most animals, metallothioneins (MTs)—small, cysteine-rich proteins that bind d10 metal ions (Zn(II), Cd(II), or Cu(I)) in clusters. Three MT homologues are known for Lumbricus rubellus, the common red earthworm, one of which, wMT-2, is strongly induced by exposure [...] Read more.
Earthworms express, as most animals, metallothioneins (MTs)—small, cysteine-rich proteins that bind d10 metal ions (Zn(II), Cd(II), or Cu(I)) in clusters. Three MT homologues are known for Lumbricus rubellus, the common red earthworm, one of which, wMT-2, is strongly induced by exposure of worms to cadmium. This study concerns composition, metal binding affinity and metal-dependent protein folding of wMT-2 expressed recombinantly and purified in the presence of Cd(II) and Zn(II). Crucially, whilst a single Cd7wMT-2 species was isolated from wMT-2-expressing E. coli cultures supplemented with Cd(II), expressions in the presence of Zn(II) yielded mixtures. The average affinities of wMT-2 determined for either Cd(II) or Zn(II) are both within normal ranges for MTs; hence, differential behaviour cannot be explained on the basis of overall affinity. Therefore, the protein folding properties of Cd- and Zn-wMT-2 were compared by 1H NMR spectroscopy. This comparison revealed that the protein fold is better defined in the presence of cadmium than in the presence of zinc. These differences in folding and dynamics may be at the root of the differential behaviour of the cadmium- and zinc-bound protein in vitro, and may ultimately also help in distinguishing zinc and cadmium in the earthworm in vivo. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Article
Does Variation of the Inter-Domain Linker Sequence Modulate the Metal Binding Behaviour of Helix pomatia Cd-Metallothionein?
Int. J. Mol. Sci. 2016, 17(1), 6; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010006 - 22 Dec 2015
Cited by 3 | Viewed by 3072
Abstract
Snail metallothioneins (MTs) constitute an ideal model to study structure/function relationships in these metal-binding polypeptides. Helix pomatia harbours three MT isoforms: the highly specific CdMT and CuMT, and an unspecific Cd/CuMT, which represent paralogous proteins with extremely different metal binding preferences while sharing [...] Read more.
Snail metallothioneins (MTs) constitute an ideal model to study structure/function relationships in these metal-binding polypeptides. Helix pomatia harbours three MT isoforms: the highly specific CdMT and CuMT, and an unspecific Cd/CuMT, which represent paralogous proteins with extremely different metal binding preferences while sharing high sequence similarity. Preceding work allowed assessing that, although, the Cys residues are responsible for metal ion coordination, metal specificity or preference is achieved by diversification of the amino acids interspersed between them. The metal-specific MT polypeptides fold into unique, energetically-optimized complexes of defined metal content, when binding their cognate metal ions, while they produce a mixture of complexes, none of them representing a clear energy minimum, with non-cognate metal ions. Another critical, and so far mostly unexplored, region is the stretch linking the individual MT domains, each of which represents an independent metal cluster. In this work, we have designed and analyzed two HpCdMT constructs with substituted linker segments, and determined their coordination behavior when exposed to both cognate and non-cognate metal ions. Results unequivocally show that neither length nor composition of the inter-domain linker alter the features of the Zn(II)- and Cd(II)-complexes, but surprisingly that they influence their ability to bind Cu(I), the non-cognate metal ion. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Article
Modulation of the PI3K/Akt Pathway and Bcl-2 Family Proteins Involved in Chicken’s Tubular Apoptosis Induced by Nickel Chloride (NiCl2)
Int. J. Mol. Sci. 2015, 16(9), 22989-23011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160922989 - 23 Sep 2015
Cited by 27 | Viewed by 3123
Abstract
Exposure of people and animals to environments highly polluted with nickel (Ni) can cause pathologic effects. Ni compounds can induce apoptosis, but the mechanism and the pathway of Ni compounds-induced apoptosis are unclear. We evaluated the alterations of apoptosis, mitochondrial membrane potential (MMP), [...] Read more.
Exposure of people and animals to environments highly polluted with nickel (Ni) can cause pathologic effects. Ni compounds can induce apoptosis, but the mechanism and the pathway of Ni compounds-induced apoptosis are unclear. We evaluated the alterations of apoptosis, mitochondrial membrane potential (MMP), phosphoinositide-3-kinase (PI3K)/serine-threonine kinase (Akt) pathway, and Bcl-2 family proteins induced by nickel chloride (NiCl2) in the kidneys of broiler chickens, using flow cytometry, terminal deoxynucleotidyl transferase 2ʹ-deoxyuridine 5ʹ-triphosphate dUTP nick end-labeling (TUNEL), immunohistochemstry and quantitative real-time polymerase chain reaction (qRT-PCR). We found that dietary NiCl2 in excess of 300 mg/kg resulted in a significant increase in apoptosis, which was associated with decrease in MMP, and increase in apoptosis inducing factor (AIF) and endonuclease G (EndoG) protein and mRNA expression. Concurrently, NiCl2 inhibited the PI3K/Akt pathway, which was characterized by decreasing PI3K, Akt1 and Akt2 mRNA expression levels. NiCl2 also reduced the protein and mRNA expression of anti-apoptotic Bcl-2 and Bcl-xL and increased the protein and mRNA expression of pro-apoptotic Bax and Bak. These results show that NiCl2 causes mitochondrial-mediated apoptosis by disruption of MMP and increased expression of AIF and EndoG mRNA and protein, and that the underlying mechanism of MMP loss involves the Bcl-2 family proteins modulation and PI3K/Akt pathway inhibition. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review

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Review
Canine Models for Copper Homeostasis Disorders
Int. J. Mol. Sci. 2016, 17(2), 196; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020196 - 04 Feb 2016
Cited by 16 | Viewed by 3352
Abstract
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis [...] Read more.
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review
Molecular Mechanisms of Nickel Allergy
Int. J. Mol. Sci. 2016, 17(2), 202; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020202 - 02 Feb 2016
Cited by 67 | Viewed by 7838
Abstract
Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human [...] Read more.
Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human patients. Here, the immunological and molecular mechanisms of metal allergy are described based on the findings of previous studies, including those that were recently published. In addition, the adsorption and excretion of various metals, in particular nickel, is discussed to further understand the pathogenesis of metal allergy. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review
Cadmium Protection Strategies—A Hidden Trade-Off?
Int. J. Mol. Sci. 2016, 17(1), 139; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010139 - 21 Jan 2016
Cited by 53 | Viewed by 3578
Abstract
Cadmium (Cd) is a non-essential transition metal which is introduced into the biosphere by various anthropogenic activities. Environmental pollution with Cd poses a major health risk and Cd toxicity has been extensively researched over the past decades. This review aims at changing the [...] Read more.
Cadmium (Cd) is a non-essential transition metal which is introduced into the biosphere by various anthropogenic activities. Environmental pollution with Cd poses a major health risk and Cd toxicity has been extensively researched over the past decades. This review aims at changing the perspective by discussing protection mechanisms available to counteract a Cd insult. Antioxidants, induction of antioxidant enzymes, and complexation of Cd to glutathione (GSH) and metallothionein (MT) are the most potent protective measures to cope with Cd-induced oxidative stress. Furthermore, protection mechanisms include prevention of endoplasmic reticulum (ER) stress, mitophagy and metabolic stress, as well as expression of chaperones. Pre-exposure to Cd itself, or co-exposure to other metals or trace elements can improve viability under Cd exposure and cells have means to reduce Cd uptake and improve Cd removal. Finally, environmental factors have negative or positive effects on Cd toxicity. Most protection mechanisms aim at preventing cellular damage. However, this might not be possible without trade-offs like an increased risk of carcinogenesis. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review
Iron Homeostasis in Health and Disease
Int. J. Mol. Sci. 2016, 17(1), 130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010130 - 20 Jan 2016
Cited by 133 | Viewed by 8780
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review
The Complex Relationship between Metals and Carbonic Anhydrase: New Insights and Perspectives
Int. J. Mol. Sci. 2016, 17(1), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010127 - 19 Jan 2016
Cited by 36 | Viewed by 3109
Abstract
Carbonic anhydrase is a ubiquitous metalloenzyme, which catalyzes the reversible hydration of CO2 to HCO3 and H+. Metals play a key role in the bioactivity of this metalloenzyme, although their relationships with CA have not been completely clarified [...] Read more.
Carbonic anhydrase is a ubiquitous metalloenzyme, which catalyzes the reversible hydration of CO2 to HCO3 and H+. Metals play a key role in the bioactivity of this metalloenzyme, although their relationships with CA have not been completely clarified to date. The aim of this review is to explore the complexity and multi-aspect nature of these relationships, since metals can be cofactors of CA, but also inhibitors of CA activity and modulators of CA expression. Moreover, this work analyzes new insights and perspectives that allow translating new advances in basic science on the interaction between CA and metals to applications in several fields of research, ranging from biotechnology to environmental sciences. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review
Possible Immune Regulation of Natural Killer T Cells in a Murine Model of Metal Ion-Induced Allergic Contact Dermatitis
Int. J. Mol. Sci. 2016, 17(1), 87; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010087 - 12 Jan 2016
Cited by 6 | Viewed by 4057
Abstract
Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is [...] Read more.
Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is unavailable. We have previously established novel murine models of metal allergy and found accumulation of both metal-specific T cells and natural killer (NK) T cells in the inflamed skin. In our novel models of metal allergy, skin hypersensitivity responses were induced through repeated sensitizations by administration of metal chloride and lipopolysaccharide into the mouse groin followed by metal chloride challenge in the footpad. These models enabled us to investigate the precise mechanisms of the immune responses of metal allergy in the inflamed skin. In this review, we summarize the immune responses in several murine models of metal allergy and describe which antigen-specific responses occur in the inflamed skin during allergic contact dermatitis in terms of the T cell receptor. In addition, we consider the immune regulation of accumulated NK T cells in metal ion–induced allergic contact dermatitis. Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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Review
The Metals in the Biological Periodic System of the Elements: Concepts and Conjectures
Int. J. Mol. Sci. 2016, 17(1), 66; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010066 - 05 Jan 2016
Cited by 94 | Viewed by 5257
Abstract
A significant number of chemical elements are either essential for life with known functions, or present in organisms with poorly defined functional outcomes. We do not know all the essential elements with certainty and we know even less about the functions of apparently [...] Read more.
A significant number of chemical elements are either essential for life with known functions, or present in organisms with poorly defined functional outcomes. We do not know all the essential elements with certainty and we know even less about the functions of apparently non-essential elements. In this article, I discuss a basis for a biological periodic system of the elements and that biochemistry should include the elements that are traditionally part of inorganic chemistry and not only those that are in the purview of organic chemistry. A biological periodic system of the elements needs to specify what “essential” means and to which biological species it refers. It represents a snapshot of our present knowledge and is expected to undergo further modifications in the future. An integrated approach of biometal sciences called metallomics is required to understand the interactions of metal ions, the biological functions that their chemical structures acquire in the biological system, and how their usage is fine-tuned in biological species and in populations of species with genetic variations (the variome). Full article
(This article belongs to the Special Issue Metal Metabolism in Animals)
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