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Homeostasis: Metals and Cellular Redox and Immunity Status
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Homeostasis: Metals and Cellular Redox and Immunity Status

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 13909

Special Issue Editors

Prof. Dr. Bernhard Michalke

E-Mail Website
Guest Editor
Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich-German Research Center for Environmental Health, 85764 Neuherberg, Germany
Interests: trace elements; transition metals; bioinorganic chemistry; environmental medicine; neurotoxicology; oxidative stress; Fe2+ and Fe3+ (im-)balance; interference with ROS defense systems (TXNRD-; GPX-; Se-species systems); cell function; homeostasis; zinc mediated disease immunity
Dr. Vivek Venkataramani

E-Mail Website
Guest Editor
1. Department of Medicine II, Hematology/Oncology, University Hospital, Frankfurt, 60590 Frankfurt am Main, Germany
2. Institute of Pathology, University Medical Center Göttingen (UMG), 37075 Göttingen, Germany
Interests: redoxbiology; Iron homeostasis; cancer biology; Alzheimer’s disease

Special Issue Information

Dear Colleagues,

Trace elements, particularly transition metals such as Fe, Ni, Cu, Co, Mn, and Zn, are essential inorganic factors for the reliable function of biochemical processes in life. These metals play various essential roles in the catalyzation of many biological reactions, modulation of protein structure and function, sensing reactive oxygen or nitrogen species, and transferrence of electrons. Intra-cellularly, machineries have evolved to tightly control the levels of these transition metals and use them for the synthesis of organometallic cofactors. They act as key-elements in enzymes or metal-carrying metabolites; however, in much lower amounts, they can play a role as free cations with different oxidation states, where Ni, Co and Zn appear as divalent cations, while others can have different oxidation states such as Fe(II) - Fe(III), Cu(I) - Cu(II) or Mn with valence states II -VII. In a balanced metabolism and homeostasis, the cellular metalloenzyme equipment works reliably according to the actual cellular, biochemical requirements and the free redox-active transition elements maintain a balanced redox status. However, an imbalance in the homeostasis of any of these transition metal ions, or their usage for the biogenesis of cofactors, could have detrimental impacts. This may result in detrimental metabolic cascades, leading to the generation of reactive oxigen species, loss of active defense systems (such as Zn-Cu-SOD or Se-enzymes like GPX4), lipid peroxidation and cellular death, or to dramatic shifts in the molecular mechanisms responsible for effective immune defense. These effects are associated with the pathogenesis of inflammation, neurodegeneration, cancer, metabolic disorders such as interferred fat metabolism or diabetes and other severe diseases.

This Special Issue aims to cover the homeostasis of transition metals and the molecular mechanisms of interfered homeostasis during the pathogenesis of severe diseases such as cancer, neurodegeneration (PD, AD, etc.), as well as with respect to shifts in immunity regulation. The localization of these elements in cellular compartments under pathologic conditions is welcome, too, as well as novel single-cell ICP-MS investigations. In this context, submissions from all groups working at the interface of bioinorganic chemistry, cell biology, and cell development using different biological models are welcome.

Prof. Dr. Bernhard Michalke
Dr. Vivek Venkataramani
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Trace elements
  • Transition Metals
  • Bioinorganic Chemistry
  • Environmental Medicine
  • Neurotoxicology
  • Cellular Redox Status Oxidative Stress
  • Cell Function
  • Homeostasis
  • Disease Immunity

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

3 pages, 165 KiB  
Editorial
Editorial to the Special Issue “Homeostasis: Metals and Cellular Redox and Immunity Status”
by Bernhard Michalke and Vivek Venkataramani
Int. J. Mol. Sci. 2023, 24(5), 4889; https://doi.org/10.3390/ijms24054889 - 03 Mar 2023
Viewed by 969
Abstract
It is with great pleasure that we introduce this Special Issue on “Homeostasis: Metals and Cellular Redox and Immunity Status” [...] Full article
(This article belongs to the Special Issue Homeostasis: Metals and Cellular Redox and Immunity Status)

Research

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14 pages, 1996 KiB  
Article
Synaptic Activity Regulates Mitochondrial Iron Metabolism to Enhance Neuronal Bioenergetics
by Paula Tena-Morraja, Guillem Riqué-Pujol, Claudia Müller-Sánchez, Manuel Reina, Ofelia M. Martínez-Estrada and Francesc X. Soriano
Int. J. Mol. Sci. 2023, 24(2), 922; https://doi.org/10.3390/ijms24020922 - 04 Jan 2023
Cited by 3 | Viewed by 1967
Abstract
Synaptic activity is the main energy-consuming process in the central nervous system. We are beginning to understand how energy is supplied and used during synaptic activity by neurons. However, the long-term metabolic adaptations associated with a previous episode of synaptic activity are not [...] Read more.
Synaptic activity is the main energy-consuming process in the central nervous system. We are beginning to understand how energy is supplied and used during synaptic activity by neurons. However, the long-term metabolic adaptations associated with a previous episode of synaptic activity are not well understood. Herein, we show that an episode of synaptic activity increases mitochondrial bioenergetics beyond the duration of the synaptic activity by transcriptionally inducing the expression of iron metabolism genes with the consequent enhancement of cellular and mitochondrial iron uptake. Iron is a necessary component of the electron transport chain complexes, and its chelation or knockdown of mitochondrial iron transporter Mfrn1 blocks the activity-mediated bioenergetics boost. We found that Mfrn1 expression is regulated by the well-known regulator of synaptic plasticity CREB, suggesting the coordinated expression of synaptic plasticity programs with those required to meet the associated increase in energetic demands. Full article
(This article belongs to the Special Issue Homeostasis: Metals and Cellular Redox and Immunity Status)
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18 pages, 3262 KiB  
Article
Differences and Interactions in Placental Manganese and Iron Transfer across an In Vitro Model of Human Villous Trophoblasts
by Vivien Michaelis, Leonie Aengenheister, Max Tuchtenhagen, Jörg Rinklebe, Franziska Ebert, Tanja Schwerdtle, Tina Buerki-Thurnherr and Julia Bornhorst
Int. J. Mol. Sci. 2022, 23(6), 3296; https://doi.org/10.3390/ijms23063296 - 18 Mar 2022
Cited by 8 | Viewed by 1875
Abstract
Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although [...] Read more.
Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes. Full article
(This article belongs to the Special Issue Homeostasis: Metals and Cellular Redox and Immunity Status)
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21 pages, 11866 KiB  
Article
High Iron and Iron Household Protein Contents in Perineuronal Net-Ensheathed Neurons Ensure Energy Metabolism with Safe Iron Handling
by Anja Reinert, Tilo Reinert, Thomas Arendt and Markus Morawski
Int. J. Mol. Sci. 2022, 23(3), 1634; https://doi.org/10.3390/ijms23031634 - 31 Jan 2022
Cited by 2 | Viewed by 2604
Abstract
A subpopulation of neurons is less vulnerable against iron-induced oxidative stress and neurodegeneration. A key feature of these neurons is a special extracellular matrix composition that forms a perineuronal net (PN). The PN has a high affinity to iron, which suggests an adapted [...] Read more.
A subpopulation of neurons is less vulnerable against iron-induced oxidative stress and neurodegeneration. A key feature of these neurons is a special extracellular matrix composition that forms a perineuronal net (PN). The PN has a high affinity to iron, which suggests an adapted iron sequestration and metabolism of the ensheathed neurons. Highly active, fast-firing neurons—which are often ensheathed by a PN—have a particular high metabolic demand, and therefore may have a higher need in iron. We hypothesize that PN-ensheathed neurons have a higher intracellular iron concentration and increased levels of iron proteins. Thus, analyses of cellular and regional iron and the iron proteins transferrin (Tf), Tf receptor 1 (TfR), ferritin H/L (FtH/FtL), metal transport protein 1 (MTP1 aka ferroportin), and divalent metal transporter 1 (DMT1) were performed on Wistar rats in the parietal cortex (PC), subiculum (SUB), red nucleus (RN), and substantia nigra (SNpr/SNpc). Neurons with a PN (PN+) have higher iron concentrations than neurons without a PN: PC 0.69 mM vs. 0.51 mM, SUB 0.84 mM vs. 0.69 mM, SN 0.71 mM vs. 0.63 mM (SNpr)/0.45 mM (SNpc). Intracellular Tf, TfR and MTP1 contents of PN+ neurons were consistently increased. The iron concentration of the PN itself is not increased. We also determined the percentage of PN+ neurons: PC 4%, SUB 5%, SNpr 45%, RN 86%. We conclude that PN+ neurons constitute a subpopulation of resilient pacemaker neurons characterized by a bustling iron metabolism and outstanding iron handling capabilities. These properties could contribute to the low vulnerability of PN+ neurons against iron-induced oxidative stress and degeneration. Full article
(This article belongs to the Special Issue Homeostasis: Metals and Cellular Redox and Immunity Status)
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Review

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16 pages, 1564 KiB  
Review
The Oncopig as an Emerging Model to Investigate Copper Regulation in Cancer
by Alyssa L. Carlson, Jaime Carrazco-Carrillo, Aaron Loder, Lobna Elkhadragy, Kyle M. Schachtschneider and Teresita Padilla-Benavides
Int. J. Mol. Sci. 2022, 23(22), 14012; https://doi.org/10.3390/ijms232214012 - 13 Nov 2022
Cited by 1 | Viewed by 2205
Abstract
Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel [...] Read more.
Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel strategies against cancer. Cu and its network of regulatory proteins are involved in many different contextual aspects of cancer from driving cell signaling, modulating cell cycle progression, establishing the epithelial-mesenchymal transition, and promoting tumor growth and metastasis. Human cancer research in general requires refined models to bridge the gap between basic science research and meaningful clinical trials. Classic studies in cultured cancer cell lines and animal models such as mice and rats often present caveats when extended to humans due to inherent genetic and physiological differences. However, larger animal models such as pigs are emerging as more appropriate tools for translational research as they present more similarities with humans in terms of genetics, anatomical structures, organ sizes, and pathological manifestations of diseases like cancer. These similarities make porcine models well-suited for addressing long standing questions in cancer biology as well as in the arena of novel drug and therapeutic development against human cancers. With the emergent roles of Cu in human health and pathology, the pig presents an emerging and valuable model to further investigate the contributions of this metal to human cancers. The Oncopig Cancer Model is a transgenic swine model that recapitulates human cancer through development of site and cell specific tumors. In this review, we briefly outline the relationship between Cu and cancer, and how the novel Oncopig Cancer Model may be used to provide a better understanding of the mechanisms and causal relationships between Cu and molecular targets involved in cancer. Full article
(This article belongs to the Special Issue Homeostasis: Metals and Cellular Redox and Immunity Status)
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22 pages, 1405 KiB  
Review
Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level
by Bernhard Michalke
Int. J. Mol. Sci. 2022, 23(11), 6109; https://doi.org/10.3390/ijms23116109 - 29 May 2022
Cited by 11 | Viewed by 3173
Abstract
Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are [...] Read more.
Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are of interest in medical research. This review summarized exciting combinations of sophisticated sample delivery systems hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS), enabling a broadening of information beyond the well-established outstanding detection capability. Deeper insights into pathological disease processes or intracellular distribution of active substances were provided, enabling a better understanding of biological processes and their dynamics. Examples were presented from spatial elemental mapping in tissue, cells, or spheroids, also considering elemental tagging. The use of natural or artificial tags for drug monitoring was shown. In the context of oxidative stress and ferroptosis iron, redox speciation gained importance. Quantification methods for Fe2+, Fe3+, and ferritin-bound iron were introduced. In Wilson’s disease, free and exchangeable copper play decisive roles; the respective paragraph provided information about hyphenated Cu speciation techniques, which provide their fast and reliable quantification. Finally, single cell ICP-MS provides highly valuable information on cell-to-cell variance, insights into uptake of metal-containing drugs, and their accumulation and release on the single-cell level. Full article
(This article belongs to the Special Issue Homeostasis: Metals and Cellular Redox and Immunity Status)
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