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Dysregulation of Calcium Signalling in Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 March 2021) | Viewed by 44280

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Special Issue Editor

Dr. Saverio Marchi

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Guest Editor

Department of Clinical and Molecular Sciences, Marche Polytechnic University, 60126 Ancona, Italy
Interests: calcium; mitochondria; Mitochondrial Ca2+ Uniporter (MCU) complex; ER-mitochondria contacts; Mitochondria-Associated Membranes (MAMs); Ca2+-mediated apoptosis

Special Issue Information

Dear Colleagues,

Calcium is the major second messenger inside the cell and acts as the most prominent signaler in a plethora of biological processes. Its homeostasis is preserved by a sophisticated system of channels, pumps, and exchangers, which ensure a low cytoplasmic Ca2+ concentration at resting conditions and prompt Ca2+ elevation upon specific stimulations.

Importantly, Ca2+ regulation is not symmetrical throughout the cell, and different subcellular districts, such as endoplasmic reticulum, mitochondria or lysosomes, are equipped with peculiar Ca2+ regulating machinery. In the last years, fantastic advances have been made in the molecular characterization of novel Ca2+ players or in the identification of unexpected Ca2+ signaling routes. It is now clear that Ca2+ alterations in a specific organelle or mutations in Ca2+ transporters and/or Ca2+-related pathways have a huge impact on the activities and functionalities of the entire cell. Therefore, it is not surprising that Ca2+ dyshomeostasis or deregulation of a single Ca2+-permeable channel have been associated with multiple pathological scenarios, including cardiovascular and neurological defects, metabolic disorders, muscular diseases, and cancers.

This Special Issue of Cells is dedicated to the role of imbalanced Ca2+ signaling in disease. Contributions in the form of original experimental articles, up-to-date reviews, or short communications are welcome. We hope that this collection of papers may help the readers to point out the contribution and the mechanistic role of Ca2+ in different pathological contexts.

Dr. Saverio Marchi
Guest Editor

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Keywords

Calcium
intracellular organelles
plasma membrane
store-operated Ca2+ entry (SOCE)
inositol 1,4,5 trisphosphate receptors (IP3Rs)
sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)
mitochondrial calcium uniporter (MCU)
sodium/calcium exchanger
ORAI and STIM proteins
mitochondrial permeability transition pore (mPTP)
TRP channels
cardiovascular diseases
neurodegenerative diseases
metabolic diseases
ageing
muscular diseases
cancer

Published Papers (11 papers)

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Research

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23 pages, 5509 KiB

Open AccessArticle

Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

by Osama M. Elzamzamy, Brandon E. Johnson, Wei-Chih Chen, Gangqing Hu, Reinhold Penner and Lori A. Hazlehurst

Cells 2021, 10(6), 1490; https://doi.org/10.3390/cells10061490 - 13 Jun 2021

Cited by 5 | Viewed by 2659

Abstract

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca²⁺ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca²⁺ and Na⁺ influx. However, replacing extracellular Na⁺ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca²⁺ reduced both MTI-101-induced Ca²⁺ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca²⁺ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca²⁺ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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17 pages, 9795 KiB

Open AccessArticle

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells

by Heejin Lee, Oh-Bin Kwon, Jae-Eon Lee, Yong-Hyun Jeon, Dong-Seok Lee, Sang-Hyun Min and Jun-Woo Kim

Cells 2021, 10(4), 918; https://doi.org/10.3390/cells10040918 - 16 Apr 2021

Cited by 11 | Viewed by 2789

Abstract

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV⁺/PI⁺ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/β-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/β-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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21 pages, 4527 KiB

Open AccessArticle

Lysophosphatidic Acid-Activated Calcium Signaling Is Elevated in Red Cells from Sickle Cell Disease Patients

by Jue Wang, Laura Hertz, Sandra Ruppenthal, Wassim El Nemer, Philippe Connes, Jeroen S. Goede, Anna Bogdanova, Lutz Birnbaumer and Lars Kaestner

Cells 2021, 10(2), 456; https://doi.org/10.3390/cells10020456 - 20 Feb 2021

Cited by 10 | Viewed by 3163

Abstract

(1) Background: It is known that sickle cells contain a higher amount of Ca²⁺ compared to healthy red blood cells (RBCs). The increased Ca²⁺ is associated with the most severe symptom of sickle cell disease (SCD), the vaso-occlusive crisis (VOC). The Ca²⁺ entry pathway received the name of P_sickle but its molecular identity remains only partly resolved. We aimed to map the involved Ca²⁺ signaling to provide putative pharmacological targets for treatment. (2) Methods: The main technique applied was Ca²⁺ imaging of RBCs from healthy donors, SCD patients and a number of transgenic mouse models in comparison to wild-type mice. Life-cell Ca²⁺ imaging was applied to monitor responses to pharmacological targeting of the elements of signaling cascades. Infection as a trigger of VOC was imitated by stimulation of RBCs with lysophosphatidic acid (LPA). These measurements were complemented with biochemical assays. (3) Results: Ca²⁺ entry into SCD RBCs in response to LPA stimulation exceeded that of healthy donors. LPA receptor 4 levels were increased in SCD RBCs. Their activation was followed by the activation of G_i protein, which in turn triggered opening of TRPC6 and Ca_V2.1 channels via a protein kinase Cα and a MAP kinase pathway, respectively. (4) Conclusions: We found a new Ca²⁺ signaling cascade that is increased in SCD patients and identified new pharmacological targets that might be promising in addressing the most severe symptom of SCD, the VOC. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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21 pages, 2070 KiB

Open AccessArticle

The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells

by Syed Islamuddin Shah and Ghanim Ullah

Cells 2020, 9(6), 1520; https://doi.org/10.3390/cells9061520 - 22 Jun 2020

Cited by 6 | Viewed by 2936

Abstract

Mitochondrial Ca²⁺ ([Ca²⁺]_M) uptake through its Ca²⁺ uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca²⁺ signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca²⁺ influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca²⁺ ([Ca²⁺]_C), [Ca²⁺]_M, and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca²⁺ buffering proteins, the separation between mitochondrion and Ca²⁺-releasing stores, and the duration of opening of Ca²⁺-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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16 pages, 2542 KiB

Open AccessArticle

Knockout of the Mitochondrial Calcium Uniporter Strongly Suppresses Stimulus-Metabolism Coupling in Pancreatic Acinar Cells but Does Not Reduce Severity of Experimental Acute Pancreatitis

by Michael Chvanov, Svetlana Voronina, Xiaoying Zhang, Svetlana Telnova, Robert Chard, Yulin Ouyang, Jane Armstrong, Helen Tanton, Muhammad Awais, Diane Latawiec, Robert Sutton, David N. Criddle and Alexei V. Tepikin

Cells 2020, 9(6), 1407; https://doi.org/10.3390/cells9061407 - 5 Jun 2020

Cited by 11 | Viewed by 3222

Abstract

Acute pancreatitis is a frequent disease that lacks specific drug treatment. Unravelling the molecular mechanisms of acute pancreatitis is essential for the development of new therapeutics. Several inducers of acute pancreatitis trigger sustained Ca²⁺ increases in the cytosol and mitochondria of pancreatic acinar cells. The mitochondrial calcium uniporter (MCU) mediates mitochondrial Ca²⁺ uptake that regulates bioenergetics and plays an important role in cell survival, damage and death. Aberrant Ca²⁺ signaling and mitochondrial damage in pancreatic acinar cells have been implicated in the initiation of acute pancreatitis. The primary aim of this study was to assess the involvement of the MCU in experimental acute pancreatitis. We found that pancreatic acinar cells from MCU^−/− mice display dramatically reduced mitochondrial Ca²⁺ uptake. This is consistent with the drastic changes of stimulus-metabolism coupling, manifested by the reduction of mitochondrial NADH/FAD⁺ responses to cholecystokinin and in the decrease of cholecystokinin-stimulated oxygen consumption. However, in three experimental models of acute pancreatitis (induced by caerulein, taurolithocholic acid 3-sulfate or palmitoleic acid plus ethanol), MCU knockout failed to reduce the biochemical and histological changes characterizing the severity of local and systemic damage. A possible explanation of this surprising finding is the redundancy of damaging mechanisms activated by the inducers of acute pancreatitis. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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17 pages, 2124 KiB

Open AccessArticle

Acute Induction of Translocon-Mediated Ca²⁺ Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury

by Ribal Al-Mawla, Mallory Ducrozet, Nolwenn Tessier, Lucille Païta, Bruno Pillot, Yves Gouriou, Camille Villedieu, Zeina Harhous, Alexandre Paccalet, Claire Crola Da Silva, Michel Ovize, Gabriel Bidaux, Sylvie Ducreux and Fabien Van Coppenolle

Cells 2020, 9(5), 1319; https://doi.org/10.3390/cells9051319 - 25 May 2020

Cited by 10 | Viewed by 3287

Abstract

During myocardial infarction, dysregulation of Ca²⁺ homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca²⁺ leak channels are thought to be key regulators of the reticular Ca²⁺ homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca²⁺ leak channel, the translocon, also known as translocation channel, could be a relevant target against ischemia/reperfusion-mediated heart injury. To achieve this objective, we first used an intramyocardial adenoviral strategy to express biosensors in order to assess Ca²⁺ variations in freshly isolated adult mouse cardiomyocytes to show that translocon is a functional reticular Ca²⁺ leak channel. Interestingly, translocon activation by puromycin mobilized a ryanodine receptor (RyR)-independent reticular Ca²⁺ pool and did not affect the excitation–concentration coupling. Second, puromycin pretreatment decreased mitochondrial Ca²⁺ content and slowed down the mitochondrial permeability transition pore (mPTP) opening and the rate of cytosolic Ca²⁺ increase during hypoxia. Finally, this translocon pre-activation also protected cardiomyocytes after in vitro hypoxia reoxygenation and reduced infarct size in mice submitted to in vivo ischemia-reperfusion. Altogether, our report emphasizes the role of translocon in cardioprotection and highlights a new paradigm in cardioprotection by functionally uncoupling the RyR-dependent Ca²⁺ stores and translocon-dependent Ca²⁺ stores. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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22 pages, 3728 KiB

Open AccessArticle

A Mathematical Model of Lysosomal Ion Homeostasis Points to Differential Effects of Cl⁻ Transport in Ca²⁺ Dynamics

by Rosario Astaburuaga, Orlando Daniel Quintanar Haro, Tobias Stauber and Angela Relógio

Cells 2019, 8(10), 1263; https://doi.org/10.3390/cells8101263 - 16 Oct 2019

Cited by 9 | Viewed by 5787

Abstract

The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in keeping proper ion homeostasis have pathological consequences. Accordingly, several human diseases are caused by the dysfunction of ion transporters. These include osteopetrosis, caused by the dysfunction of Cl⁻/H⁺ exchange by the lysosomal transporter ClC-7. To better understand how chloride transport affects lysosomal ion homeostasis and how its disruption impinges on lysosomal function, we developed a mathematical model of lysosomal ion homeostasis including Ca²⁺ dynamics. The model recapitulates known biophysical properties of ClC-7 and enables the investigation of its differential activation kinetics on lysosomal ion homeostasis. We show that normal functioning of ClC-7 supports the acidification process, is associated with increased luminal concentrations of sodium, potassium, and chloride, and leads to a higher Ca²⁺ uptake and release. Our model highlights the role of ClC-7 in lysosomal acidification and shows the existence of differential Ca²⁺ dynamics upon perturbations of Cl⁻/H⁺ exchange and its activation kinetics, with possible pathological consequences. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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Review

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30 pages, 3869 KiB

Open AccessFeature PaperReview

Mitochondrial Ca²⁺ Signaling in Health, Disease and Therapy

by Lorenzo Modesti, Alberto Danese, Veronica Angela Maria Vitto, Daniela Ramaccini, Gianluca Aguiari, Roberta Gafà, Giovanni Lanza, Carlotta Giorgi and Paolo Pinton

Cells 2021, 10(6), 1317; https://doi.org/10.3390/cells10061317 - 25 May 2021

Cited by 58 | Viewed by 8056

Abstract

The divalent cation calcium (Ca²⁺) is considered one of the main second messengers inside cells and acts as the most prominent signal in a plethora of biological processes. Its homeostasis is guaranteed by an intricate and complex system of channels, pumps, and exchangers. In this context, by regulating cellular Ca²⁺ levels, mitochondria control both the uptake and release of Ca²⁺. Therefore, at the mitochondrial level, Ca²⁺ plays a dual role, participating in both vital physiological processes (ATP production and regulation of mitochondrial metabolism) and pathophysiological processes (cell death, cancer progression and metastasis). Hence, it is not surprising that alterations in mitochondrial Ca²⁺ (mCa²⁺) pathways or mutations in Ca²⁺ transporters affect the activities and functions of the entire cell. Indeed, it is widely recognized that dysregulation of mCa²⁺ signaling leads to various pathological scenarios, including cancer, neurological defects and cardiovascular diseases (CVDs). This review summarizes the current knowledge on the regulation of mCa²⁺ homeostasis, the related mechanisms and the significance of this regulation in physiology and human diseases. We also highlight strategies aimed at remedying mCa²⁺ dysregulation as promising therapeutical approaches. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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14 pages, 2006 KiB

Open AccessReview

The Discovery of Naringenin as Endolysosomal Two-Pore Channel Inhibitor and Its Emerging Role in SARS-CoV-2 Infection

by Antonella D’Amore, Antonella Gradogna, Fioretta Palombi, Velia Minicozzi, Matteo Ceccarelli, Armando Carpaneto and Antonio Filippini

Cells 2021, 10(5), 1130; https://doi.org/10.3390/cells10051130 - 7 May 2021

Cited by 20 | Viewed by 3872

Abstract

The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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15 pages, 1555 KiB

Open AccessReview

Role of the TRP Channels in Pancreatic Ductal Adenocarcinoma Development and Progression

by Gonçalo Mesquita, Natalia Prevarskaya, Albrecht Schwab and V’yacheslav Lehen’kyi

Cells 2021, 10(5), 1021; https://doi.org/10.3390/cells10051021 - 26 Apr 2021

Cited by 10 | Viewed by 2617

Abstract

The transient receptor potential channels (TRPs) have been related to several different physiologies that range from a role in sensory physiology (including thermo- and osmosensation) to a role in some pathologies like cancer. The great diversity of functions performed by these channels is represented by nine sub-families that constitute the TRP channel superfamily. From the mid-2000s, several reports have shown the potential role of the TRP channels in cancers of multiple origin. The pancreatic cancer is one of the deadliest cancers worldwide. Its prevalence is predicted to rise further. Disappointingly, the treatments currently used are ineffective. There is an urgency to find new ways to counter this disease and one of the answers may lie in the ion channels belonging to the superfamily of TRP channels. In this review, we analyse the existing knowledge on the role of TRP channels in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The functions of these channels in other cancers are also considered. This might be of interest for an extrapolation to the pancreatic cancer in an attempt to identify potential therapeutic interventions. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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14 pages, 8190 KiB

Open AccessReview

Ca²⁺ Signaling by TRPV4 Channels in Respiratory Function and Disease

by Suhasini Rajan, Christian Schremmer, Jonas Weber, Philipp Alt, Fabienne Geiger and Alexander Dietrich

Cells 2021, 10(4), 822; https://doi.org/10.3390/cells10040822 - 6 Apr 2021

Cited by 18 | Viewed by 4584

Abstract

Members of the transient receptor potential (TRP) superfamily are broadly expressed in our body and contribute to multiple cellular functions. Most interestingly, the fourth member of the vanilloid family of TRP channels (TRPV4) serves different partially antagonistic functions in the respiratory system. This review highlights the role of TRPV4 channels in lung fibroblasts, the lung endothelium, as well as the alveolar and bronchial epithelium, during physiological and pathophysiological mechanisms. Data available from animal models and human tissues confirm the importance of this ion channel in cellular signal transduction complexes with Ca²⁺ ions as a second messenger. Moreover, TRPV4 is an excellent therapeutic target with numerous specific compounds regulating its activity in diseases, like asthma, lung fibrosis, edema, and infections. Full article

(This article belongs to the Special Issue Dysregulation of Calcium Signalling in Disease)

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