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Calcium Homeostasis of Cells in Health and Disease: Third Edition
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Calcium Homeostasis of Cells in Health and Disease: Third Edition

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

Deadline for manuscript submissions: 20 May 2026 | Viewed by 4487

Special Issue Editors

Dr. Péter Szentesi

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Guest Editor
Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98., H-4002 Debrecen, Hungary
Interests: skeletal muscle; intracellular calcium; excitation contraction coupling; muscle force; myopathies; aging; antioxidants
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. László Csernoch

E-Mail Website
Guest Editor
1. Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
2. HUN-REN Cell Physiology Research Group, University of Debrecen, 4032 Debrecen, Hungary
Interests: calcium signaling; skeletal muscle; excitation-contraction coupling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue, “Calcium Homeostasis of Cells in Health and Disease: 2nd Edition”.

Whether in health or disease, calcium ions (Ca2+) play an important role in stimuli by responding to the processes of cells as a second messenger. In this process, the body maintains a low intracellular Ca2+ concentration at rest and mobilizes Ca2+ in response to stimuli, which activates cellular functions. This second-messenger role of Ca2+ was first discovered during the excitation–contraction coupling of skeletal muscle. Since then, the characteristics of Ca2+ as a second messenger (the variety of its targets, its ability to achieve quick and substantial transient and oscillatory mobilization, and its ability to cause localized and generalized cell responses) have been widely studied.

Although calcium has been extensively investigated in a variety of cells, many of its features are still uncertain; for example, what is its role in physiological and pathological circumstances? A few studies have shown that the Ca2+ homeostasis of cells changes during development and as they age. The latter is becoming increasingly important, as the Earth’s population is increasingly living longer. Thus, aging is a hot topic in research on humans. In addition, alterations in calcium homeostasis can occur in several diseases. New technological challenges and innovations in the use of calcium sensors have deepened our knowledge in this field, enabling us to study calcium concentrations outside and inside cells and even in cell organelles.

The aim of this Special Issue is to collect novel data regarding the role of calcium in the functioning of cells. We encourage the submission of manuscripts presenting innovative strategies to maintain and/or improve cell functions in aging and diseases.

Dr. Péter Szentesi
Prof. Dr. László Csernoch
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 250 words) can be sent to the Editorial Office for assessment.

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.

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Keywords

  • Ca2+
  • calcium homeostasis
  • calcium-binding proteins
  • aging
  • disease

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Related Special Issues

Published Papers (6 papers)

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Research

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22 pages, 5599 KB  
Article
Calmodulin Interaction Interface with Plasma Membrane Ca2+-ATPase Isoforms: An Integrative Bioinformatic Analysis
by Miguel Martínez-Fresneda, Esteban Lizano, Gabriela Echeverría-Garcés, Andres Herrera-Yela, Danna Feijóo, Grecia Victoria Vivas-Colmenares, Alvaro López-Zaplana, Leda Pedelini, Marta Mendoza, Juan Carlos Navarro and Jose Ruben Ramírez-Iglesias
Int. J. Mol. Sci. 2025, 26(23), 11750; https://doi.org/10.3390/ijms262311750 - 4 Dec 2025
Viewed by 295
Abstract
Plasma membrane Ca2+-ATPases (PMCA) are activated by calmodulin (CaM) via a C-terminal calmodulin-binding domain, CaMBD. Although specific mutations in this domain have been linked to disease, the broader impact of alternative substitutions across the interface remains unexplored. We applied an integrative [...] Read more.
Plasma membrane Ca2+-ATPases (PMCA) are activated by calmodulin (CaM) via a C-terminal calmodulin-binding domain, CaMBD. Although specific mutations in this domain have been linked to disease, the broader impact of alternative substitutions across the interface remains unexplored. We applied an integrative in silico workflow to test six substitutions within CaMBD positions 1–18, L5R, N6I, I8T, V14E/D, and F18S, across PMCA isoforms 1–4. CaMBD sequences were aligned across isoforms, and candidates for substitutions were selected by conservation and nucleotide feasibility, prioritizing conserved or co-evolutionarily relevant sites, with substitutions possible by single-nucleotide change. PolyPhen-2 screened the impact of the substitutions on the protein functionality, the DisGeNET database was used to contextualize ATP2B genes with clinical phenotypes, and structural models plus binding free energy changes were estimated with AlphaFold3, FoldX, and MutaBind2. Effects were isoform and subregion dependent, with the strongest weakening toward the CaMBD C-terminus. V14E/D and F18S showed the largest and consistent predicted destabilization, consistent with disruption of conserved hydrophobic anchors. I8T and L5R had mixed outcomes depending on isoform, while N6I presented various scenarios with no clear effect. PolyPhen-2 classified most tested substitutions as damaging. Gene-disease evidence linked ATP2B to neurological, endocrine, and oncologic phenotypes, consistent with roles in Ca2+ homeostasis. Overall, CaMBD appears highly sensitive to perturbation, with distal positions 14–18 particularly vulnerable to substitutions that can destabilize CaM binding and potentially impair PMCA-mediated Ca2+ clearance in susceptible tissues. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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18 pages, 3161 KB  
Article
A Semi-Automatic Tool for the Standardized Analysis of Fluorescent Intensity Changes in Polarized Cells
by Fruzsina Fazekas, Tibor Zelles and Eszter Berekméri
Int. J. Mol. Sci. 2025, 26(20), 9987; https://doi.org/10.3390/ijms26209987 - 14 Oct 2025
Viewed by 369
Abstract
Imaging of intracellular messengers, like calcium, is one of the most reliable methods to follow real-time changes in several aspects of cellular activity, like receptor activation. However, the analysis could be influenced and biased by several factors like the location, shape, and size [...] Read more.
Imaging of intracellular messengers, like calcium, is one of the most reliable methods to follow real-time changes in several aspects of cellular activity, like receptor activation. However, the analysis could be influenced and biased by several factors like the location, shape, and size of the regions of interest (ROIs) and by the detection and correction of the movement of the preparation. Programs which are provided by the manufacturers are expensive and cannot be shared by collaborators. Many self-made programs have been implemented lately which have in-built cell recognizer ROI identification functions. These programs focus on the soma of the cells and neglect the processes, because in full tissue preparation finding cells is still challenging. Subcellular imaging experiments are still rare. To the best of our knowledge there is no program which can automatically define ROIs for subcellular imaging experiments even in single indicated cells with complex morphology. We developed and validated a program to address this gap using simple and understandable mathematical methods for ROI determination and simple statistics for movement correction. Validation experiments were conducted on cochlear Deiters’ cells. Deiters’ cells have processed morphology which connects two fluid compartments in the cochlea. Because of the function and the fine morphology of the cell, it could be interesting to examine the subcellular Ca2+ handling mechanisms of it. Test impulses were activated by ATP. With some limitations the program successfully fulfilled its purpose. As a free, easily understandable, and open-source program, we hope it will help to analyze and plan subcellular experiments. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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16 pages, 2994 KB  
Article
Structural Insights and Calcium-Switching Mechanism of Fasciola hepatica Calcium-Binding Protein FhCaBP4
by Byeongmin Shin, Seonha Park, Ingyo Park, Hongchul Shin, Kyuhyeon Bang, Sulhee Kim and Kwang Yeon Hwang
Int. J. Mol. Sci. 2025, 26(15), 7584; https://doi.org/10.3390/ijms26157584 - 5 Aug 2025
Viewed by 759
Abstract
Fasciola hepatica remains a global health and economic concern, and treatment still relies heavily on triclabendazole. At the parasite–host interface, F. hepatica calcium-binding proteins (FhCaBPs) have a unique EF-hand/DLC-like domain fusion found only in trematodes. This makes it a parasite-specific target for small [...] Read more.
Fasciola hepatica remains a global health and economic concern, and treatment still relies heavily on triclabendazole. At the parasite–host interface, F. hepatica calcium-binding proteins (FhCaBPs) have a unique EF-hand/DLC-like domain fusion found only in trematodes. This makes it a parasite-specific target for small compounds and vaccinations. To enable novel therapeutic strategies, we report the first elevated-resolution structure of a full-length FhCaBP4. The apo structure was determined at 1.93 Å resolution, revealing a homodimer architecture that integrates an N-terminal, calmodulin-like, EF-hand pair with a C-terminal dynein light chain (DLC)-like domain. Structure-guided in silico mutagenesis identified a flexible, 16-residue β4–β5 loop (LTGSYWMKFSHEPFMS) with an FSHEPF core that demonstrates greater energetic variability than its FhCaBP2 counterpart, likely explaining the distinct ligand-binding profiles of these paralogs. Molecular dynamics simulations and AlphaFold3 modeling suggest that EF-hand 2 acts as the primary calcium-binding site, with calcium coordination inducing partial rigidification and modest expansion of the protein structure. Microscale thermophoresis confirmed calcium as the major ligand, while calmodulin antagonists bound with lower affinity and praziquantel demonstrated no interaction. Thermal shift assays revealed calcium-dependent stabilization and a merger of biphasic unfolding transitions. These results suggest that FhCaBP4 functions as a calcium-responsive signaling hub, with an allosterically coupled EF-hand–DLC interface that could serve as a structurally tractable platform for drug targeting in trematodes. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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29 pages, 3549 KB  
Article
Physiological Muscle Function Is Controlled by the Skeletal Endocannabinoid System in Murine Skeletal Muscles
by Nyamkhuu Ganbat, Zoltán Singlár, Péter Szentesi, Elena Lilliu, Zoltán Márton Kohler, László Juhász, Anikó Keller-Pintér, Xaver Koenig, Fabio Arturo Iannotti, László Csernoch and Mónika Sztretye
Int. J. Mol. Sci. 2025, 26(11), 5291; https://doi.org/10.3390/ijms26115291 - 30 May 2025
Cited by 1 | Viewed by 1654
Abstract
The endocannabinoid system (ECS) is known to regulate crucial bodily functions, including healthy muscle activity. However, its precise roles in normal skeletal muscle function and the development of muscle disorders remain unclear. Previously, we developed a tamoxifen-inducible, skeletal muscle-specific CB1 receptor knockdown [...] Read more.
The endocannabinoid system (ECS) is known to regulate crucial bodily functions, including healthy muscle activity. However, its precise roles in normal skeletal muscle function and the development of muscle disorders remain unclear. Previously, we developed a tamoxifen-inducible, skeletal muscle-specific CB1 receptor knockdown (skmCB1-KD) mouse model using the Cre/LoxP system. In this study, we aimed to clarify the mechanisms behind the observed reduction in muscle force generation in these mice. To investigate this, we analyzed calcium dynamics following electrical stimulation-induced muscle fatigue, assessed store-operated calcium entry (SOCE), and performed functional analysis of mitochondrial respiration. Our findings suggest that the reduced muscle performance observed in vivo likely arises from interconnected alterations in ATP production by mitochondria. Moreover, in skmCB1-KD mice, we detected a significant decrease in a component of the respiratory chain (complex IV) and a slowed dissipation of mitochondrial membrane potential upon the addition of an un-coupler (FCCP). Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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Review

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19 pages, 1777 KB  
Review
Intracellular Calcium as a Regulator of Polarization and Target Reprogramming of Macrophages
by Marina Y. Pogonyalova, Daniil Y. Popov and Andrey Y. Vinokurov
Int. J. Mol. Sci. 2025, 26(24), 11901; https://doi.org/10.3390/ijms262411901 - 10 Dec 2025
Viewed by 264
Abstract
Macrophage metabolic plasticity providing their polarization towards classically (M1) or alternatively (M2) activated cells is an important element of the initiation, development, and resolving or inflammation-linked pathologies. The prevalence of M1 or M2 types of macrophages during different stages of diseases supports increased [...] Read more.
Macrophage metabolic plasticity providing their polarization towards classically (M1) or alternatively (M2) activated cells is an important element of the initiation, development, and resolving or inflammation-linked pathologies. The prevalence of M1 or M2 types of macrophages during different stages of diseases supports increased inflammation and phagocytosis or tissue repair, respectively. An imbalance leading to a shift toward an M1- or M2-dominant state is associated with a chronic pathological process. This characterizes the regulation of macrophage phenotypes as a prospective strategy in the treatment of various diseases and makes it relevant to a deep understanding of the mechanisms defining cell polarization. According to the central role of calcium signaling in cell metabolism, changes in calcium homeostasis are closely linked to the regulation of polarization. The exact balance between calcium flows across plasma and intracellular membranes provided by a number of receptors and channels, as well as the differences in the calcium-buffering capability of endoplasmic reticulum and mitochondria, are able to influence macrophage polarization towards an M1 or M2 phenotype. This review focuses on the role of the calcium homeostasis system in macrophage functionality and calcium-induced changes in macrophage metabolism that forms the basis of target disease therapy. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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15 pages, 700 KB  
Review
The Ca2+ Bridge: From Neurons to Circuits in Rett Syndrome
by Luis Molina Calistro, Yennyfer Arancibia, Javiera Alarcón and Rodrigo Flavio Torres
Int. J. Mol. Sci. 2025, 26(21), 10490; https://doi.org/10.3390/ijms262110490 - 29 Oct 2025
Viewed by 648
Abstract
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused primarily by mutations in the gene encoding the methyl-CpG-binding protein 2 (Mecp2). Mecp2 binds to methylated cytosines, playing a crucial role in chromatin organization and transcriptional regulation. At the neurobiological level, RTT is characterized [...] Read more.
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused primarily by mutations in the gene encoding the methyl-CpG-binding protein 2 (Mecp2). Mecp2 binds to methylated cytosines, playing a crucial role in chromatin organization and transcriptional regulation. At the neurobiological level, RTT is characterized by dendritic spine dysgenesis and altered excitation–inhibition balance, drawing attention to the mechanisms that scale from mutations in a nuclear protein to altered neuronal connectivity. Although Mecp2 dysfunction disrupts multiple neuronal processes, emerging evidence highlights altered calcium (Ca2+) signaling as a central contributor to RTT pathophysiology. This review explores the link between Mecp2 and Ca2+ regulation by highlighting how Mecp2 affects Ca2+-dependent transcriptional pathways, while Ca2+ modulates Mecp2 function by inducing post-translational modifications. We discuss this crosstalk in light of evidence from RTT models, with a particular focus on the brain-derived neurotrophic factor BDNF-miR132-Mecp2 axis and the dysregulation of ryanodine receptors (RyRs). Additionally, we examine how these perturbations contribute to the reduced structural plasticity and the altered activity-driven gene expression that characterizes RTT. Understanding the intersection between Mecp2 function and Ca2+ homeostasis will provide critical insights into RTT pathogenesis and potential therapeutic targets aimed at restoring neuronal connectivity. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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