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Mitochondrial Calcium Signaling

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 62343

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Special Issue Editors

Dr. Anna Raffaello

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Guest Editor

Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: mitochondria; calcium; mitochondrial calcium uniporter; skeletal muscle physiology

Dr. Denis Vecellio Reane

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Guest Editor

Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: mitochondria; calcium; mitochondrial calcium uniporter; skeletal muscle physiology

Special Issue Information

Dear Colleagues,

Mitochondrial calcium has long been recognized as a fundamental signal in a plethora of cellular functions, ranging from the control of metabolism and ATP production to the regulation of cell death.

In the last ten years, we have witnessed an explosion of basic and translational research studies aiming to clarify the role of this crucial signal molecule. This was possible thanks to the identification of the long-sought molecular identity of the mitochondrial calcium uniporter complex that allowed the development of several tools to alter mitochondrial calcium.

The aim of this Special Issue is to bring together reviews and original papers on the composition and regulation of the complex and on the physiopathological function of mitochondrial calcium uptake.

We believe that there would be great interest in such a topic due to the regulation and stoichiometry of the components of the channel, the regulation of its activity, and the role in tissue homeostasis.

Dr. Anna Raffaello
Dr. Denis Vecellio Reane
Guest Editors

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Keywords

mitochondrial calcium uniporter
calcium signaling
EF-hand proteins
mitochondria
signal transduction
ion channels
calcium dysregulation
calcium probes

Published Papers (12 papers)

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Research

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12 pages, 1333 KiB

Open AccessArticle

Different Sensitivity of Control and MICU1- and MICU2-Ablated Trypanosoma cruzi Mitochondrial Calcium Uniporter Complex to Ruthenium-Based Inhibitors

by Mayara S. Bertolini and Roberto Docampo

Int. J. Mol. Sci. 2020, 21(23), 9316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239316 - 07 Dec 2020

Cited by 1 | Viewed by 2499

Abstract

The mitochondrial Ca²⁺ uptake in trypanosomatids shares biochemical characteristics with that of animals. However, the composition of the mitochondrial Ca²⁺ uniporter complex (MCUC) in these parasites is quite peculiar, suggesting lineage-specific adaptations. In this work, we compared the inhibitory activity of ruthenium red (RuRed) and Ru360, the most commonly used MCUC inhibitors, with that of the recently described inhibitor Ru265, on Trypanosoma cruzi, the agent of Chagas disease. Ru265 was more potent than Ru360 and RuRed in inhibiting mitochondrial Ca²⁺ transport in permeabilized cells. When dose-response effects were investigated, an increase in sensitivity for Ru360 and Ru265 was observed in TcMICU1-KO and TcMICU2-KO cells as compared with control cells. In the presence of RuRed, a significant increase in sensitivity was observed only in TcMICU2-KO cells. However, application of Ru265 to intact cells did not affect growth and respiration of epimastigotes, mitochondrial Ca²⁺ uptake in Rhod-2-labeled intact cells, or attachment to host cells and infection by trypomastigotes, suggesting a low permeability for this compound in trypanosomes. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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18 pages, 2727 KiB

Open AccessArticle

The Effect of Deflazacort Treatment on the Functioning of Skeletal Muscle Mitochondria in Duchenne Muscular Dystrophy

by Mikhail V. Dubinin, Eugeny Yu. Talanov, Kirill S. Tenkov, Vlada S. Starinets, Natalia V. Belosludtseva and Konstantin N. Belosludtsev

Int. J. Mol. Sci. 2020, 21(22), 8763; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228763 - 19 Nov 2020

Cited by 22 | Viewed by 8078

Abstract

Duchenne muscular dystrophy (DMD) is a severe hereditary disease caused by a lack of dystrophin, a protein essential for myocyte integrity. Mitochondrial dysfunction is reportedly responsible for DMD. This study examines the effect of glucocorticoid deflazacort on the functioning of the skeletal-muscle mitochondria of dystrophin-deficient mdx mice and WT animals. Deflazacort administration was found to improve mitochondrial respiration of mdx mice due to an increase in the level of ETC complexes (complexes III and IV and ATP synthase), which may contribute to the normalization of ATP levels in the skeletal muscle of mdx animals. Deflazacort treatment improved the rate of Ca²⁺ uniport in the skeletal muscle mitochondria of mdx mice, presumably by affecting the subunit composition of the calcium uniporter of organelles. At the same time, deflazacort was found to reduce the resistance of skeletal mitochondria to MPT pore opening, which may be associated with a change in the level of ANT2 and CypD. In this case, deflazacort also affected the mitochondria of WT mice. The paper discusses the mechanisms underlying the effect of deflazacort on the functioning of mitochondria and contributing to the improvement of the muscular function of mdx mice. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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11 pages, 2765 KiB

Open AccessArticle

Mitochondrial Ca²⁺ Dynamics in MCU Knockout C. elegans Worms

by Pilar Álvarez-Illera, Paloma García-Casas, Rosalba I Fonteriz, Mayte Montero and Javier Alvarez

Int. J. Mol. Sci. 2020, 21(22), 8622; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228622 - 16 Nov 2020

Cited by 14 | Viewed by 2787

Abstract

Mitochondrial [Ca²⁺] plays an important role in the regulation of mitochondrial function, controlling ATP production and apoptosis triggered by mitochondrial Ca²⁺ overload. This regulation depends on Ca²⁺ entry into the mitochondria during cell activation processes, which is thought to occur through the mitochondrial Ca²⁺ uniporter (MCU). Here, we have studied the mitochondrial Ca²⁺ dynamics in control and MCU-defective C. elegans worms in vivo, by using worms expressing mitochondrially-targeted YC3.60 yellow cameleon in pharynx muscle. Our data show that the small mitochondrial Ca²⁺ oscillations that occur during normal physiological activity of the pharynx were very similar in both control and MCU-defective worms, except for some kinetic differences that could mostly be explained by changes in neuronal stimulation of the pharynx. However, direct pharynx muscle stimulation with carbachol triggered a large and prolonged increase in mitochondrial [Ca²⁺] that was much larger in control worms than in MCU-defective worms. This suggests that MCU is necessary for the fast mitochondrial Ca²⁺ uptake induced by large cell stimulations. However, low-amplitude mitochondrial Ca²⁺ oscillations occurring under more physiological conditions are independent of the MCU and use a different Ca²⁺ pathway. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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Review

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14 pages, 950 KiB

Open AccessReview

Bcl-2 Family of Proteins in the Control of Mitochondrial Calcium Signalling: An Old Chap with New Roles

by Jordan L. Morris, Germain Gillet, Julien Prudent and Nikolay Popgeorgiev

Int. J. Mol. Sci. 2021, 22(7), 3730; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073730 - 02 Apr 2021

Cited by 38 | Viewed by 8572

Abstract

Bcl-2 family proteins are considered as one of the major regulators of apoptosis. Indeed, this family is known to control the mitochondrial outer membrane permeabilization (MOMP): a central step in the mitochondrial pathway of apoptosis. However, in recent years Bcl-2 family members began to emerge as a new class of intracellular calcium (Ca²⁺) regulators. At mitochondria-ER contacts (MERCs) these proteins are able to interact with major Ca²⁺ transporters, thus controlling mitochondrial Ca²⁺ homeostasis and downstream Ca²⁺ signalling pathways. Beyond the regulation of cell survival, this Bcl-2-dependent control over the mitochondrial Ca²⁺ dynamics has far-reaching consequences on the physiology of the cell. Here, we review how the Bcl-2 family of proteins mechanistically regulate mitochondrial Ca²⁺ homeostasis and how this regulation orchestrates cell death/survival decisions as well as the non-apoptotic process of cell migration. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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16 pages, 3933 KiB

Open AccessReview

Mitochondrial Calcium Signaling in Pancreatic β-Cell

by Anna Weiser, Jerome N. Feige and Umberto De Marchi

Int. J. Mol. Sci. 2021, 22(5), 2515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052515 - 03 Mar 2021

Cited by 10 | Viewed by 3017

Abstract

Accumulation of calcium in energized mitochondria of pancreatic β-cells is emerging as a crucial process for pancreatic β-cell function. β-cell mitochondria sense and shape calcium signals, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion during nutrient stimulation. Here, we describe the role of mitochondrial calcium signaling in pancreatic β-cell function. We report the latest pharmacological and genetic findings, including the first mitochondrial calcium-targeted intervention strategies developed to modulate pancreatic β-cell function and their potential relevance in the context of diabetes. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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12 pages, 1189 KiB

Open AccessReview

Intracellular Ca²⁺ Signaling in Protozoan Parasites: An Overview with a Focus on Mitochondria

by Pedro H. Scarpelli, Mateus F. Pecenin and Celia R. S. Garcia

Int. J. Mol. Sci. 2021, 22(1), 469; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010469 - 05 Jan 2021

Cited by 13 | Viewed by 3989

Abstract

Ca²⁺ signaling has been involved in controling critical cellular functions such as activation of proteases, cell death, and cell cycle control. The endoplasmatic reticulum plays a significant role in Ca²⁺ storage inside the cell, but mitochondria have long been recognized as a fundamental Ca²⁺ pool. Protozoan parasites such as Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma cruzi display a Ca²⁺ signaling toolkit with similarities to higher eukaryotes, including the participation of mitochondria in Ca²⁺-dependent signaling events. This review summarizes the most recent knowledge in mitochondrial Ca²⁺ signaling in protozoan parasites, focusing on the mechanism involved in mitochondrial Ca²⁺ uptake by pathogenic protists. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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13 pages, 2447 KiB

Open AccessReview

Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria

by Debanjali Dasgupta, Philippe Delmotte and Gary C. Sieck

Int. J. Mol. Sci. 2021, 22(1), 363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010363 - 31 Dec 2020

Cited by 14 | Viewed by 3308

Abstract

The effects of airway inflammation on airway smooth muscle (ASM) are mediated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). In this review article, we will provide a unifying hypothesis for a homeostatic response to airway inflammation that mitigates oxidative stress and thereby provides resilience to ASM. Previous studies have shown that acute exposure to TNFα increases ASM force generation in response to muscarinic stimulation (hyper-reactivity) resulting in increased ATP consumption and increased tension cost. To meet this increased energetic demand, mitochondrial O₂ consumption and oxidative phosphorylation increases but at the cost of increased reactive oxygen species (ROS) production (oxidative stress). TNFα-induced oxidative stress results in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and mitochondria of ASM. In the ER, TNFα selectively phosphorylates inositol-requiring enzyme 1 alpha (pIRE1α) triggering downstream splicing of the transcription factor X-box binding protein 1 (XBP1s); thus, activating the pIRE1α/XBP1s ER stress pathway. Protein unfolding in mitochondria also triggers an unfolded protein response (^mtUPR). In our conceptual framework, we hypothesize that activation of these pathways is homeostatically directed towards mitochondrial remodeling via an increase in peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) expression, which in turn triggers: (1) mitochondrial fragmentation (increased dynamin-related protein-1 (Drp1) and reduced mitofusin-2 (Mfn2) expression) and mitophagy (activation of the Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin mitophagy pathway) to improve mitochondrial quality; (2) reduced Mfn2 also results in a disruption of mitochondrial tethering to the ER and reduced mitochondrial Ca²⁺ influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O₂ consumption and oxidative phosphorylation and reduced ROS formation by individual mitochondrion, while still meeting the increased ATP demand. Thus, the energetic load of hyper-reactivity is shared across the mitochondrial pool within ASM cells. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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22 pages, 32835 KiB

Open AccessReview

Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing

by Chi-Hsiao Yeh, Yi-Ju Chou, Cheng-Heng Kao and Ting-Fen Tsai

Int. J. Mol. Sci. 2020, 21(23), 9238; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239238 - 03 Dec 2020

Cited by 21 | Viewed by 3726

Abstract

The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca²⁺ control; (d) disturbance to mitochondria–lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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17 pages, 715 KiB

Open AccessReview

The Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases

by Kerry C. Ryan, Zahra Ashkavand and Kenneth R. Norman

Int. J. Mol. Sci. 2020, 21(23), 9153; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239153 - 01 Dec 2020

Cited by 53 | Viewed by 7930

Abstract

Calcium signaling is essential for neuronal function, and its dysregulation has been implicated across neurodegenerative diseases, including Alzheimer’s disease (AD). A close reciprocal relationship exists between calcium signaling and mitochondrial function. Growing evidence in a variety of AD models indicates that calcium dyshomeostasis drastically alters mitochondrial activity which, in turn, drives neurodegeneration. This review discusses the potential pathogenic mechanisms by which calcium impairs mitochondrial function in AD, focusing on the impact of calcium in endoplasmic reticulum (ER)–mitochondrial communication, mitochondrial transport, oxidative stress, and protein homeostasis. This review also summarizes recent data that highlight the need for exploring the mechanisms underlying calcium-mediated mitochondrial dysfunction while suggesting potential targets for modulating mitochondrial calcium levels to treat neurodegenerative diseases such as AD. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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18 pages, 1560 KiB

Open AccessReview

ER–Mitochondria Contact Sites Reporters: Strengths and Weaknesses of the Available Approaches

by Flavia Giamogante, Lucia Barazzuol, Marisa Brini and Tito Calì

Int. J. Mol. Sci. 2020, 21(21), 8157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218157 - 31 Oct 2020

Cited by 24 | Viewed by 4877

Abstract

Organelle intercommunication represents a wide area of interest. Over the last few decades, increasing evidence has highlighted the importance of organelle contact sites in many biological processes including Ca²⁺ signaling, lipid biosynthesis, apoptosis, and autophagy but also their involvement in pathological conditions. ER–mitochondria tethering is one of the most investigated inter-organelle communications and it is differently modulated in response to several cellular conditions including, but not limited to, starvation, Endoplasmic Reticulum (ER) stress, and mitochondrial shape modifications. Despite many studies aiming to understand their functions and how they are perturbed under different conditions, approaches to assess organelle proximity are still limited. Indeed, better visualization and characterization of contact sites remain a fascinating challenge. The aim of this review is to summarize strengths and weaknesses of the available methods to detect and quantify contact sites, with a main focus on ER–mitochondria tethering. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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14 pages, 887 KiB

Open AccessReview

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

by Lo Lai and Hongyu Qiu

Int. J. Mol. Sci. 2020, 21(20), 7689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207689 - 17 Oct 2020

Cited by 17 | Viewed by 3702

Abstract

Calcium ion (Ca²⁺) plays a critical role in the cardiac mitochondria function. Ca²⁺ entering the mitochondria is necessary for ATP production and the contractile activity of cardiomyocytes. However, excessive Ca²⁺ in the mitochondria results in mitochondrial dysfunction and cell death. Mitochondria maintain Ca²⁺ homeostasis in normal cardiomyocytes through a comprehensive regulatory mechanism by controlling the uptake and release of Ca²⁺ in response to the cellular demand. Understanding the mechanism of modulating mitochondrial Ca²⁺ homeostasis in the cardiomyocyte could bring new insights into the pathogenesis of cardiac disease and help developing the strategy to prevent the heart from damage at an early stage. In this review, we summarized the latest findings in the studies on the cardiac mitochondrial Ca²⁺ homeostasis, focusing on the regulation of mitochondrial calcium uptake, which acts as a double-edged sword in the cardiac function. Specifically, we discussed the dual roles of mitochondrial Ca²⁺ in mitochondrial activity and the impact on cardiac function, the molecular basis and regulatory mechanisms, and the potential future research interest. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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32 pages, 6074 KiB

Open AccessReview

Diabetes Mellitus, Mitochondrial Dysfunction and Ca²⁺-Dependent Permeability Transition Pore

by Konstantin N. Belosludtsev, Natalia V. Belosludtseva and Mikhail V. Dubinin

Int. J. Mol. Sci. 2020, 21(18), 6559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186559 - 08 Sep 2020

Cited by 61 | Viewed by 9018

Abstract

Diabetes mellitus is one of the most common metabolic diseases in the developed world, and is associated either with the impaired secretion of insulin or with the resistance of cells to the actions of this hormone (type I and type II diabetes, respectively). In both cases, a common pathological change is an increase in blood glucose—hyperglycemia, which eventually can lead to serious damage to the organs and tissues of the organism. Mitochondria are one of the main targets of diabetes at the intracellular level. This review is dedicated to the analysis of recent data regarding the role of mitochondrial dysfunction in the development of diabetes mellitus. Specific areas of focus include the involvement of mitochondrial calcium transport systems and a pathophysiological phenomenon called the permeability transition pore in the pathogenesis of diabetes mellitus. The important contribution of these systems and their potential relevance as therapeutic targets in the pathology are discussed. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling)

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