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Membrane Dynamics and Calcium Signaling
Abstract
This book describes the newest discoveries on calcium signaling occurring at the cellular
and intracellular membranes, often exerted in so called microdomains. Calcium entry and
release, its interaction with proteins and resulting events on proteins and organelles are
comprehensively depicted by leading experts in the field.
Knowledge about details of these highly dynamic processes rapidly increased in recent
years, the book therefore provides a timely summary on the processes of calcium
signaling and related membrane dynamics; it is aimed at students and researchers in biochemistry and cell biology
... The cellular concentration of free Ca 2+ regulates an array of biochemical reactions and is crucial for signal transduction (Rizzuto, Duchen & Pozzan, 2004;Elustondo et al., 2017;Herst et al., 2017;Krebs, 2017;Santulli, 2017;Giorgi et al., 2018a;Giorgi, Marchi & Pinton, 2018b;Del Re et al., 2019;Glaser et al., 2019;Hausenloy et al., 2020). Mitochondria are fundamental to cellular energy metabolism, supplying energy in the form of ATP and affecting cell physiology through the regulation of Ca 2+ homeostasis (Picard, Wallace & Burelle, 2016;Krebs, 2017). ...
... The cellular concentration of free Ca 2+ regulates an array of biochemical reactions and is crucial for signal transduction (Rizzuto, Duchen & Pozzan, 2004;Elustondo et al., 2017;Herst et al., 2017;Krebs, 2017;Santulli, 2017;Giorgi et al., 2018a;Giorgi, Marchi & Pinton, 2018b;Del Re et al., 2019;Glaser et al., 2019;Hausenloy et al., 2020). Mitochondria are fundamental to cellular energy metabolism, supplying energy in the form of ATP and affecting cell physiology through the regulation of Ca 2+ homeostasis (Picard, Wallace & Burelle, 2016;Krebs, 2017). Mitochondria have a large capacity to accumulate Ca 2+ and can transiently store it, thus contributing to cell calcium homeostasis. ...
... To access the mitochondrial matrix, Ca 2+ must first pass through the OMM. This membrane is permeable to ions, in particular to Ca 2+ , and to small proteins, due to the presence of a large conductance channelthe voltage-dependent anion channel (VDAC)which allows the exchange of molecules of molecular weight up to 1500 Da (Schein, Colombini & Finkelstein, 1976;Colombini & Mannella, 2012;Krebs, 2017;Becker & Wagner, 2018;Magri, Reina & de Pinto, 2018). The VDAC is responsible for Ca 2+ transport from the cytoplasm into mitochondria, with its permeability controlled by ATP and other regulatory factors. ...
In this review, we summarize current knowledge of perhaps one of the most intriguing phenomena in cell biology: the mitochondrial permeability transition pore (mPTP). This phenomenon, which was initially observed as a sudden loss of inner mitochondrial membrane impermeability caused by excessive calcium, has been studied for almost 50 years, and still no definitive answer has been provided regarding its mechanisms. From its initial consideration as an in vitro artifact to the current notion that the mPTP is a phenomenon with physiological and pathological implications, a long road has been travelled. We here summarize the role of mitochondria in cytosolic calcium control and the evolving concepts regarding the mitochondrial permeability transition (mPT) and the mPTP. We show how the evolving mPTP models and mechanisms, which involve many proposed mitochondrial protein components, have arisen from methodological advances and more complex biological models. We describe how scientific progress and methodological advances have allowed milestone discoveries on mPTP regulation and composition and its recognition as a valid target for drug development and a critical component of mitochondrial biology.
... Mitochondria operate as signaling organelles in aging and agingassociated diseases also because they influence Ca 2+ concentration in the cytosol. Although Ca 2+ ions are known as potent and versatile second messengers in signaling pathways that orchestrate many cellular processes (Berridge et al., 2000;Clapham, 2007;Krebs, 2017), they are not metabolites and, therefore, not mitobolites. However, a body of evidence discussed in this section indicates that mitochondria are essential contributors to the maintenance of cellular Ca 2+ homeostasis and that such contribution of mitochondria is linked to many aging-associated pathologies. ...
... An uptake of extracellular Ca 2+ by plasma membrane channels is the major external source of intracellular Ca 2+ (Bagur and Hajnóczky, 2017;Calì et al., 2017;Krebs, 2017), whereas the endoplasmic reticulum (ER) (sarcoplasmic reticulum in muscle cells) and lysosomes are the two largest stores and major internal sources of Ca 2+ within eukaryotic cells (Raffaello et al., 2016;Krebs, 2017;Giorgi et al., 2018). Because of the existence of the ER-mitochondria contact sites and due to the presence of Ca 2+selective channels in the mitochondrial membranes, mitochondria FIGURE 5 | Amino acids synthesized in mitochondria accelerate aging by stimulating TOR signaling. ...
... An uptake of extracellular Ca 2+ by plasma membrane channels is the major external source of intracellular Ca 2+ (Bagur and Hajnóczky, 2017;Calì et al., 2017;Krebs, 2017), whereas the endoplasmic reticulum (ER) (sarcoplasmic reticulum in muscle cells) and lysosomes are the two largest stores and major internal sources of Ca 2+ within eukaryotic cells (Raffaello et al., 2016;Krebs, 2017;Giorgi et al., 2018). Because of the existence of the ER-mitochondria contact sites and due to the presence of Ca 2+selective channels in the mitochondrial membranes, mitochondria FIGURE 5 | Amino acids synthesized in mitochondria accelerate aging by stimulating TOR signaling. ...
Recent studies have revealed that some low-molecular weight molecules produced in mitochondria are essential contributing factors to aging and aging-associated pathologies in evolutionarily distant eukaryotes. These molecules are intermediates or products of certain metabolic reactions that are activated in mitochondria in response to specific changes in the nutrient, stress, proliferation, or age status of the cell. After being released from mitochondria, these metabolites directly or indirectly change activities of a distinct set of protein sensors that reside in various cellular locations outside of mitochondria. Because these protein sensors control the efficiencies of some pro- or anti-aging cellular processes, such changes in their activities allow to create a pro- or anti-aging cellular pattern. Thus, mitochondria can function as signaling platforms that respond to certain changes in cell stress and physiology by remodeling their metabolism and releasing a specific set of metabolites known as “mitobolites.” These mitobolites then define the pace of cellular and organismal aging because they regulate some longevity-defining processes taking place outside of mitochondria. In this review, we discuss recent progress in understanding mechanisms underlying the ability of mitochondria to function as such signaling platforms in aging and aging-associated diseases.
A multitude of Ca²⁺-sensor proteins containing the specific Ca²⁺-binding motif (helix-loop-helix, called EF-hand) are of major clinical relevance in a many human diseases. Measurements of troponin, the first intracellular Ca-sensor protein to be discovered, is nowadays the “gold standard” in the diagnosis of patients with acute coronary syndrome (ACS). Mutations have been identified in calmodulin and linked to inherited ventricular tachycardia and in patients affected by severe cardiac arrhythmias. Parvalbumin, when introduced into the diseased heart by gene therapy to increase contraction and relaxation speed, is considered to be a novel therapeutic strategy to combat heart failure. S100 proteins, the largest subgroup with the EF-hand protein family, are closely associated with cardiovascular diseases, various types of cancer, inflammation, and autoimmune pathologies. The intention of this review is to summarize the clinical importance of this protein family and their use as biomarkers and potential drug targets, which could help to improve the diagnosis of human diseases and identification of more selective therapeutic interventions.
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