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• W2527503499 abstract "Ca2+ signaling is regulated by the intimate interconnection between intracellular organelles and plasma membrane channels. The ultrastructures of endoplasmic reticulum and mitochondrial Ca2+ channels have been determined. Great advances have been made in our understanding of the function and regulation of the mitochondrial calcium uniporter. Studies on endolysosomal Ca2+ signaling unravel a potential contribution of this compartment to global Ca2+ homeostasis. In recent years, rapid discoveries have been made relating to Ca2+ handling at specific organelles that have important implications for whole-cell Ca2+ homeostasis. In particular, the structures of the endoplasmic reticulum (ER) Ca2+ channels revealed by electron cryomicroscopy (cryo-EM), continuous updates on the structure, regulation, and role of the mitochondrial calcium uniporter (MCU) complex, and the analysis of lysosomal Ca2+ signaling are milestones on the route towards a deeper comprehension of the complexity of global Ca2+ signaling. In this review we summarize recent discoveries on the regulation of interorganellar Ca2+ homeostasis and its role in pathophysiology. In recent years, rapid discoveries have been made relating to Ca2+ handling at specific organelles that have important implications for whole-cell Ca2+ homeostasis. In particular, the structures of the endoplasmic reticulum (ER) Ca2+ channels revealed by electron cryomicroscopy (cryo-EM), continuous updates on the structure, regulation, and role of the mitochondrial calcium uniporter (MCU) complex, and the analysis of lysosomal Ca2+ signaling are milestones on the route towards a deeper comprehension of the complexity of global Ca2+ signaling. In this review we summarize recent discoveries on the regulation of interorganellar Ca2+ homeostasis and its role in pathophysiology. The second messenger Ca2+ regulates numerous cellular processes, including, but not limited to, muscle contraction, exocytosis, and gene transcription. The ER [or sarcoplasmic reticulum (SR) in striated muscles] is the largest Ca2+ store in the cell. While the cytosolic Ca2+ concentration ([Ca2+]cyt) at rest is about 100 nM, ER [Ca2+] can reach 1 mM, depending on the cell type. On physiological stimuli, Ca2+ is released from the ER/SR, which in turn stimulates Ca2+ influx from the plasma membrane. This rapid and sustained [Ca2+]cyt increase regulates Ca2+-dependent effector proteins (e.g., calpains, kinases, phosphatases, ion channels) and Ca2+-dependent functions. Eventually, Ca2+ is pumped back to the ER and [Ca2+]cyt returns to resting values. Specific proteins and channels contribute to the fine-tuned regulation of the whole cycle. In addition, close contacts between the ER and the plasma membrane, and the other intracellular organelles, participate in the control of Ca2+ homeostasis. In particular, mitochondria were the first organelles shown to be capable of taking up Ca2+, even before the chemiosmotic theory of mitochondrial Ca2+ accumulation (for a review see [1Rizzuto R. et al.Mitochondria as sensors and regulators of calcium signalling.Nat. Rev. Mol. Cell Biol. 2012; 13: 566-578Crossref PubMed Scopus (453) Google Scholar]). Many roles have been ascribed to Ca2+ accumulation by mitochondria [1Rizzuto R. et al.Mitochondria as sensors and regulators of calcium signalling.Nat. Rev. Mol. Cell Biol. 2012; 13: 566-578Crossref PubMed Scopus (453) Google Scholar]. Three dehydrogenases of the Krebs cycle have been shown to be modulated by Ca2+ [2Denton R.M. McCormack J.G. The role of calcium in the regulation of mitochondrial metabolism.Biochem. Soc. Trans. 1980; 8: 266-268Crossref PubMed Google Scholar], thus controlling overall cellular metabolism. Furthermore, mitochondrial Ca2+ uptake shapes cytosolic Ca2+ dynamics and mitochondrial Ca2+ overload has been associated with the apoptotic process [1Rizzuto R. et al.Mitochondria as sensors and regulators of calcium signalling.Nat. Rev. Mol. Cell Biol. 2012; 13: 566-578Crossref PubMed Scopus (453) Google Scholar]. More recently, lysosomes have been suggested to participate in the regulation of Ca2+ homeostasis acting as Ca2+ stores, but their contribution to cellular Ca2+ signaling is still debated. In recent years, important discoveries have been made relating to various aspects of Ca2+ homeostasis and to the interplay between Ca2+ stores and the cytosolic Ca2+ pool. Here we summarize the main aspects that have emerged, focusing on the mechanisms and regulation of Ca2+ signaling in the ER, mitochondria, and lysosomes. As mentioned above, the ER/SR represents the main Ca2+ store. Rapid release of Ca2+ from this compartment ensures the sustained [Ca2+]cyt rises required for specific cell functions. Recent work has contributed mechanistic details of inositol 1,4,5-trisphosphate (InsP3)-mediated Ca2+ dynamics and on the molecular structures of InsP3 receptor 1 (InsP3R1) and ryanodine receptor 1 (RyR1). Activation of phospholipase C triggers the release of InsP3 from phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. On interaction of InsP3 with its receptors (InsP3Rs) located at the ER membrane, Ca2+ is released to the cytosol (Figure 1). Ca2+ itself regulates the InsP3R open probability (Po), activating InsP3R at increasing [Ca2+] up to a specific [Ca2+] threshold while playing an inhibitory role at higher [Ca2+]. In addition, oscillatory cytosolic Ca2+ rises are characteristic responses to agonist-induced InsP3 release. The frequency of such oscillations depends on stimulus strength and determines the fine control of downstream metabolic responses. The mechanism underlying InsP3-dependent [Ca2+]cyt oscillations has been clarified only recently. Work in the Thomas laboratory has demonstrated that InsP3 and [Ca2+]cyt oscillations are mutually determined and that InsP3 fluctuations are essential for the generation of [Ca2+]cyt spikes and propagation of Ca2+ waves, in agreement with the so-called cross-coupling hypotheses [3Gaspers L.D. et al.Hormone-induced calcium oscillations depend on cross-coupling with inositol 1,4,5-trisphosphate oscillations.Cell Rep. 2014; 9: 1209-1218Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. The InsP3R family comprises three isoforms, InsP3R1, InsP3R2, and InsP3R3, that are expressed at different levels in different tissues. Of note, InsP3R1 is most abundant in neuronal cells of the central nervous system (CNS) and mutations in this gene are associated with severe CNS disorders, including ataxia. InsP3R2 is expressed in various tissues and is the most abundant isoform in cardiac muscle. InsP3Rs form heterotetramers whose activity is not simply the sum of the single isoforms constituting the channel, but rather display unique properties and responsiveness to ATP, Ca2+, and InsP3 [4Chandrasekhar R. et al.Unique regulatory properties of heterotetrameric inositol 1,4,5-trisphosphate receptors revealed by studying concatenated receptor constructs.J. Biol. Chem. 2016; 291: 4846-4860Crossref PubMed Scopus (0) Google Scholar, 5Chandrasekhar R. et al.Using concatenated subunits to investigate the functional consequences of heterotetrameric inositol 1,4,5-trisphosphate receptors.Biochem. Soc. Trans. 2015; 43: 364-370Crossref PubMed Scopus (0) Google Scholar]. In striated muscles, Ca2+ is released from the SR by the opening of RyRs. As for InsP3Rs, the RyR family includes three isoforms; that is, RyR1–3. All isoforms are abundant in CNS. In addition, RyR1 and RyR2 are highly expressed in striated muscles. RyR1 is particularly enriched in skeletal muscle and RyR2 in cardiac muscle. RyR3 is expressed in most tissues. In skeletal muscle, RyR1 opens on coupling with the voltage-gated Ca2+ channel (Cav1.1), also known as the Ca2+-dependent L-type calcium channel dihydropyridine receptor (DHPR), thus ensuring excitation–contraction (EC) coupling. In the myocardium, L-type Ca2+ channels ensure the entrance of Ca2+, which triggers the opening of RyR2 by a Ca2+-induced Ca2+-release mechanism. Mutations in RyR1 are associated with susceptibility to malignant hyperthermia, central core disease, and minicore myopathy with external ophthalmoplegia [6Jungbluth H. et al.Core myopathies.Semin. Pediatr. Neurol. 2011; 18: 239-249Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In this respect, the compound AICAR has been proposed for prophylactic treatment of heat-induced sudden death based on its ability to interact with RyR1 and reduce Ca2+ leakage independently of activation of its target AMP-activated protein kinase (AMPK) [7Lanner J.T. et al.AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation.Nat. Med. 2012; 18: 244-251Crossref PubMed Scopus (50) Google Scholar]. Mutations in the RyR3 gene have also been associated with central core disease. RyR2 mutations are linked with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia type 2. Recently, the cryo-EM structures of InsP3R1 and RyR1 have been described. InsP3Rs and RyRs are both characterized by an analogous tetrameric structure and share similar activation mechanisms. Besides the specific role of InsP3 in InsP3Rs activation, both InsP3Rs and RyRs are activated by low [Ca2+] and inhibited by high [Ca2+]. The structure of InsP3R1, solved at a resolution of 4.7 Å [8Fan G. et al.Gating machinery of InsP3R channels revealed by electron cryomicroscopy.Nature. 2015; 527: 336-341Crossref PubMed Scopus (60) Google Scholar], revealed that while the ion-conduction pore is similar to homologous tetrameric ion channels (e.g., RyRs), the gating of the channel is ensured by unique C-terminal domains facing the cytosol that interact with the InsP3-binding domain of neighboring subunits causing an allosteric rearrangement. These results are in agreement with previous studies based on microsomal membrane preparations expressing recombinant InsP3R isoforms [9Boehning D. Joseph S.K. Direct association of ligand-binding and pore domains in homo- and heterotetrameric inositol 1,4,5-trisphosphate receptors.EMBO J. 2000; 19: 5450-5459Crossref PubMed Google Scholar]. In parallel with InsP3R, the structure of RyR1 was also solved by cryo-EM, revealing a six-transmembrane ion channel characterized by an EF-hand domain for Ca2+-mediated allosteric gating and a huge cytoplasmic domain on top of each transmembrane domain [10Zalk R. et al.Structure of a mammalian ryanodine receptor.Nature. 2015; 517: 44-49Crossref PubMed Scopus (127) Google Scholar, 11Efremov R.G. et al.Architecture and conformational switch mechanism of the ryanodine receptor.Nature. 2015; 517: 39-43Crossref PubMed Scopus (104) Google Scholar, 12Yan Z. et al.Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution.Nature. 2015; 517: 50-55Crossref PubMed Scopus (150) Google Scholar]. Comparison of the InsP3R and RyR structures revealed important similarities between the two channels. Of note, although the cytoplasmic domain of RyR is much larger than that of InsP3R, the location of N-terminal regions required for the formation of functional tetramers relative to the transmembrane channel regions of the receptors is very similar. A novel ER Ca2+ channel has been shown to be encoded by the transmembrane and coiled-coil domains 1 (TMCO1) gene [13Wang Q-C. et al.TMCO1 is an ER Ca2+ load-activated Ca2+ channel.Cell. 2016; 165: 1454-1466Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. At physiological [Ca2+], TMCO1 is present as inactive monomers in the ER membrane. Above a certain [Ca2+] threshold, TMCO1 monomers form active tetrameric channels that extrude Ca2+ from the ER matrix, thus preventing ER Ca2+ overload. Mutations in the TMCO1 gene are associated to human cerebrofaciothoracic (CFT) dysplasia spectrum, which is mainly characterized by craniofacial dysmorphism, skeletal anomalies, mental retardation, and ataxia [13Wang Q-C. et al.TMCO1 is an ER Ca2+ load-activated Ca2+ channel.Cell. 2016; 165: 1454-1466Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Once Ca2+ has been released from the ER, the enhanced [Ca2+]cyt is sustained by Ca2+ influx from the extracellular milieu through SOCE. SOCE facilitates Ca2+ refilling into the ER, which is a necessary event to stop Ca2+ entry and restore resting [Ca2+]. The mechanism of SOCE is ensured by the coordinated activity of two families of proteins, STIM and ORAI. STIM1 and STIM2 are single transmembrane ER proteins with their C-terminal domains facing the cytosol [14Hogan P.G. Rao A. Store-operated calcium entry: mechanisms and modulation.Biochem. Biophys. Res. Commun. 2015; 460: 40-49Crossref PubMed Scopus (37) Google Scholar]. The ORAI family comprises cell membrane proteins that form the conductive pore of Ca2+ release-activated Ca2+ (CRAC) channels and includes ORAI1–3, each of which contains four transmembrane domains. For ORAI1–3, both N- and C-terminal domains face the cytosol [14Hogan P.G. Rao A. Store-operated calcium entry: mechanisms and modulation.Biochem. Biophys. Res. Commun. 2015; 460: 40-49Crossref PubMed Scopus (37) Google Scholar]. On ER Ca2+ depletion, STIM moves to ER–plasma membrane junctions where it interacts with ORAI, thus inducing Ca2+ influx into the ER (Figure 2). Both loss- and gain-of-function mutations in STIM and ORAI (resulting in decreased and increased Ca2+ influx, respectively) have been detected in human patients [15Lacruz R.S. Feske S. Diseases caused by mutations in ORAI1 and STIM1.Ann. N. Y. Acad. Sci. 2015; 1356: 45-79Crossref PubMed Scopus (51) Google Scholar]. Loss-of-function mutations result in severe combined immunodeficiency (SCID)-like syndrome, autoimmune diseases, myopathy, and ectodermal dysplasia, which leads to defects in sweat gland function and tooth development [15Lacruz R.S. Feske S. Diseases caused by mutations in ORAI1 and STIM1.Ann. N. Y. Acad. Sci. 2015; 1356: 45-79Crossref PubMed Scopus (51) Google Scholar]. Gain-of-function mutations cause various syndromes, all associated with myopathy and platelet defects [15Lacruz R.S. Feske S. Diseases caused by mutations in ORAI1 and STIM1.Ann. N. Y. Acad. Sci. 2015; 1356: 45-79Crossref PubMed Scopus (51) Google Scholar]. ER Ca2+ uptake exerts a buffering effect on [Ca2+]cyt, ensuring the maintenance of resting [Ca2+]cyt in the nanomolar range by the activity of sarco(endo)plasmic reticulum calcium ATPase (SERCA) (Figure 1). SERCA activity is increased upon ER/SR Ca2+ store release, allowing rapid reuptake of cytosolic Ca2+. In addition, it has been proposed that coupling between SOCE, SERCA, and InsP3 mediates Ca2+ signaling between spatially distant effectors [16Courjaret R. Machaca K. Mid-range Ca2+ signalling mediated by functional coupling between store-operated Ca2+ entry and IP3-dependent Ca2+ release.Nat. Commun. 2014; 5: 3916Crossref PubMed Scopus (0) Google Scholar]. According to this model, Ca2+ entering through SOCE is taken up in the ER by SERCA, to be released again by InsP3R to activate distal Ca2+-activated Cl− channels (CaCCs), which contribute to the regulation of cell membrane potential. The SERCA family comprises three isoforms, SERCA1–3, encoded by the ATP2A1–3 genes. SERCA1 is exclusively expressed in skeletal muscle, SERCA2 is expressed in skeletal and cardiac muscle, brain, and other tissues, and SERCA3 is ubiquitously expressed. SERCA activity is modulated by transmembrane proteins; specifically, phospholamban in the heart and sarcolipin in skeletal muscle [17Sammels E. et al.Intracellular Ca2+ storage in health and disease: a dynamic equilibrium.Cell Calcium. 2010; 47: 297-314Crossref PubMed Scopus (102) Google Scholar]. Mutations in SERCA1 are linked to Brody disease, characterized by defects in relaxation on exercise, stiffness, and cramps. Defects in the expression levels and activity of SERCA2a, one of the two SERCA2 isoforms, specifically expressed in slow-twitch myofibers and in cardiac muscle, are apparent in heart failure and phospholamban mutations have been identified in patients with cardiac hypertrophy and decreased ejection fraction [18Gorski P.A. et al.Altered myocardial calcium cycling and energetics in heart failure – a rational approach for disease treatment.Cell Metab. 2015; 21: 183-194Abstract Full Text Full Text PDF PubMed Google Scholar]. Recently, the role of a peptide named DWORF in enhancing SERCA activity in striated muscles has been reported [19Nelson B.R. et al.A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle.Science. 2016; 351: 271-275Crossref PubMed Scopus (102) Google Scholar]. Intriguingly, DWORF is encoded by a genomic region that is annotated as a long noncoding RNA. DWORF displaces inhibitory proteins from SERCA, thus increasing muscle performance. So far, DWORF is the only known direct activator of SERCA, and potential therapies for heart diseases could possibly arise from positive modulation of DWORF activity. That mitochondria accumulate high [Ca2+] on physiological stimulation has long remained counterintuitive given that, under these conditions, [Ca2+]cyt rises only from 0.1 μM to about 2–3 μM. This [Ca2+]cyt is too low to allow Ca2+ uptake by the low-affinity MCU. However, this model was revised when the existence of high [Ca2+] microdomains ([Ca2+] >10 μM) at the site of ER–mitochondria contacts was demonstrated [1Rizzuto R. et al.Mitochondria as sensors and regulators of calcium signalling.Nat. Rev. Mol. Cell Biol. 2012; 13: 566-578Crossref PubMed Scopus (453) Google Scholar]. Both interorganelle distance and contact site size have been proved to be critical parameters for Ca2+ transfer. Purification of a subcellular fraction corresponding to ER–mitochondria contacts [referred to as mitochondria-associated membranes (MAMs)] led to the identification of proteins enriched in these membrane domains [20Marchi S. et al.The endoplasmic reticulum–mitochondria connection: one touch, multiple functions.Biochim. Biophys. Acta. 2014; 1837: 461-469Crossref PubMed Scopus (0) Google Scholar]. Among them, Mitofusin 2 (Mfn2) is located at both ER and mitochondrial membranes where it forms homo- and heterotypic interactions, the latter with Mfn1 (Figure 1). Mfn2 has been reported to strengthen ER–mitochondria contacts and to facilitate mitochondrial Ca2+ uptake [21de Brito O.M. Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria.Nature. 2008; 456: 605-610Crossref PubMed Scopus (980) Google Scholar, 22Koshiba T. et al.Structural basis of mitochondrial tethering by mitofusin complexes.Science. 2004; 305: 858-862Crossref PubMed Scopus (421) Google Scholar]. However, this model has been challenged by a quantitative electron microscopy analysis demonstrating that, in Mfn2-knockout (KO) cells, ER–mitochondria contacts are increased rather than decreased [23Cosson P. et al.Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study.PLoS ONE. 2012; 7: e46293Crossref PubMed Scopus (0) Google Scholar]. Along these lines, analysis of light microscopy images taking into account the changes in organelle morphology on Mfn2 deletion further demonstrated the increase in the percentage of the mitochondrial perimeter colocalizing with the ER [24Filadi R. et al.Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling.Proc. Natl Acad. Sci. U.S.A. 2015; 112: E2174-E2181Crossref PubMed Scopus (0) Google Scholar]. The reduction in mitochondrial Ca2+ uptake previously observed in Mfn2-KO cells [21de Brito O.M. Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria.Nature. 2008; 456: 605-610Crossref PubMed Scopus (980) Google Scholar] was suggested to be due to reduced MCU expression levels in these cells [24Filadi R. et al.Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling.Proc. Natl Acad. Sci. U.S.A. 2015; 112: E2174-E2181Crossref PubMed Scopus (0) Google Scholar]. In addition, acute silencing of Mfn2, which did not affect MCU protein levels, triggered an increase in mitochondrial Ca2+ uptake [24Filadi R. et al.Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling.Proc. Natl Acad. Sci. U.S.A. 2015; 112: E2174-E2181Crossref PubMed Scopus (0) Google Scholar]. Thus, the authors concluded that Mnf2 acts as a negative regulator of ER–mitochondrial tethers, which, by reducing the number of contacts, avoids toxic Ca2+ accumulation [24Filadi R. et al.Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling.Proc. Natl Acad. Sci. U.S.A. 2015; 112: E2174-E2181Crossref PubMed Scopus (0) Google Scholar]. Overall, the role of Mfn2 at ER–mitochondria contacts remains highly debated. For the sake of brevity, we do not discuss here the many chaperones and other proteins involved in mitochondrial dynamics that participate in the regulation of ER–mitochondrial Ca2+ transfer; these have recently been reviewed elsewhere [20Marchi S. et al.The endoplasmic reticulum–mitochondria connection: one touch, multiple functions.Biochim. Biophys. Acta. 2014; 1837: 461-469Crossref PubMed Scopus (0) Google Scholar]. The molecular characterization of the uniporter complex began with the discovery of one of its regulatory subunits, mitochondrial Ca2+ uptake 1 (MICU1) [25Perocchi F. et al.MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake.Nature. 2010; 467: 291-296Crossref PubMed Scopus (0) Google Scholar], soon followed by the identification of CCDC109A, now known as the MCU, as the pore-forming subunit of the uniporter complex [26Baughman J.M. et al.Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter.Nature. 2011; 476: 341-345Crossref PubMed Scopus (661) Google Scholar, 27De Stefani D. et al.A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.Nature. 2011; 476: 336-340Crossref PubMed Scopus (692) Google Scholar] (Figure 3). In the following 5 years, we have witnessed an explosion of discoveries on the composition of the MCU complex and, more importantly, on the physiopathological roles of mitochondrial Ca2+ entry. Great advances in our understanding of the regulation of the channel come from the description of the structural properties of its components [28Oxenoid K. et al.Architecture of the mitochondrial calcium uniporter.Nature. 2016; 533: 269-273Crossref PubMed Scopus (54) Google Scholar, 29Wang L. et al.Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake.EMBO J. 2014; 33: 594-604Crossref PubMed Scopus (39) Google Scholar, 30Lee Y. et al.Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter.EMBO Rep. 2015; 16: 1318-1333Crossref PubMed Scopus (21) Google Scholar], although the complete architecture of the MCU complex is far from being solved. Recent studies have shown that the Ca2+ permeant pore comprises three proteins: the MCU, MCUb, and EMRE [31Kamer K.J. Mootha V.K. The molecular era of the mitochondrial calcium uniporter.Nat. Rev. Mol. Cell Biol. 2015; 16: 545-553Crossref PubMed Scopus (66) Google Scholar] (Figure 3). MCUb (previously known as CCDC109B) is an MCU isoform conserved in most vertebrates and in many plants but absent in other organisms where the MCU is present [32Raffaello A. et al.The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit.EMBO J. 2013; 32: 2362-2376Crossref PubMed Scopus (118) Google Scholar]. The MCU and MCUb share 50% sequence similarity and each possesses two transmembrane domains separated by a short loop that differs slightly between the two. More importantly, the MCUb isoform has a crucial amino acid substitution in the loop region (E256V) that has an impact on channeling properties. In living cells, overexpression of MCUb reduces the amplitude of [Ca2+]mit transients evoked by agonist stimulation whereas MCUb silencing elicits the opposite effect, indicating that MCUb acts as a dominant-negative subunit that incorporates into the uniporter channel and reduces its activity [32Raffaello A. et al.The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit.EMBO J. 2013; 32: 2362-2376Crossref PubMed Scopus (118) Google Scholar]. Still unclear is the function of this protein in physiopathology, although the ratio of MCU to MCUb expression, which varies greatly between tissues, might contribute to the differences in the amplitude of mitochondrial Ca2+ uptake seen in different tissues, as recently demonstrated by patch-clamp analysis [33Fieni F. et al.Activity of the mitochondrial calcium uniporter varies greatly between tissues.Nat. Commun. 2012; 3: 1317Crossref PubMed Scopus (76) Google Scholar]. More debated is the role of EMRE in the regulation of MCU channel activity [34De Stefani D. et al.Structure and function of the mitochondrial calcium uniporter complex.Biochim. Biophys. Acta. 2015; 1853: 2006-2011Crossref PubMed Scopus (33) Google Scholar]. EMRE is a 10-kDa protein that is widely expressed in most mammalian tissues and comprises a single predicted transmembrane domain with a highly acidic carboxyl terminus [35Sancak Y. et al.EMRE is an essential component of the mitochondrial calcium uniporter complex.Science. 2013; 342: 1379-1382Crossref PubMed Scopus (173) Google Scholar]. EMRE was shown to play a dual function in the regulation of MCU activity. First, it seems necessary for MCU channel activity since its silencing abrogates Ca2+ entry into mitochondria [35Sancak Y. et al.EMRE is an essential component of the mitochondrial calcium uniporter complex.Science. 2013; 342: 1379-1382Crossref PubMed Scopus (173) Google Scholar], although purified MCU is sufficient to give rise to Ca2+ currents in a planar lipid bilayer [27De Stefani D. et al.A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.Nature. 2011; 476: 336-340Crossref PubMed Scopus (692) Google Scholar]. Second, EMRE seems to also mediate the interaction between the MCU and the regulatory subunits MICU1 and MICU2 [35Sancak Y. et al.EMRE is an essential component of the mitochondrial calcium uniporter complex.Science. 2013; 342: 1379-1382Crossref PubMed Scopus (173) Google Scholar]. Of note, EMRE is not present in plants, fungi, and protozoa, where the MCU and MICU1 are expressed, suggesting that it represents a metazoan specialization. Consistently, in yeast only the heterologous expression of the human MCU – and not the Dictyostelium discoideum MCU – requires EMRE for proper MCU functioning [36Kovács-Bogdán E. et al.Reconstitution of the mitochondrial calcium uniporter in yeast.Proc. Natl Acad. Sci. U.S.A. 2014; 111: 8985-8990Crossref PubMed Scopus (0) Google Scholar]. One of the peculiar properties of mitochondrial Ca2+ uptake is the sigmoidal response to [Ca2+]cyt. Despite the steep mitochondrial membrane potential, under resting conditions Ca2+ uptake is inhibited to prevent matrix Ca2+ overload and the dissipation of membrane potential that would prevent ATP synthesis. In turn, when cells are stimulated mitochondria have to respond promptly by exponentially increasing the Ca2+-carrying capacity [37Rizzuto R. et al.Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses.Science. 1998; 280: 1763-1766Crossref PubMed Scopus (1310) Google Scholar, 38Csordás G. et al.Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria.EMBO J. 1999; 18: 96-108Crossref PubMed Scopus (354) Google Scholar, 39Csordás G. et al.Imaging interorganelle contacts and local calcium dynamics at the ER–mitochondrial interface.Mol. Cell. 2010; 39: 121-132Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. This property does not reside with the MCU itself but rather with its regulators, the Ca2+-binding EF-hand-containing proteins MICU1 and MICU2 [34De Stefani D. et al.Structure and function of the mitochondrial calcium uniporter complex.Biochim. Biophys. Acta. 2015; 1853: 2006-2011Crossref PubMed Scopus (33) Google Scholar] (Figure 3). MICU1 silencing was initially proposed to inhibit mitochondrial Ca2+ uptake [25Perocchi F. et al.MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake.Nature. 2010; 467: 291-296Crossref PubMed Scopus (0) Google Scholar]. However, the Mallilankaraman and Csordás laboratories [40Mallilankaraman K. et al.MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival.Cell. 2012; 151: 630-644Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 41Csordás G. et al.MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter.Cell Metab. 2013; 17: 976-987Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar] showed that both transient and constitutive loss of MICU1 lead to basal mitochondrial Ca2+ accumulation. This observation was confirmed by the identification of a loss-of-function mutation in the MICU1 gene in patients affected by brain and muscle disorders [42Logan C.V. et al.Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.Nat. Genet. 2014; 46: 188-193Crossref PubMed Scopus (101) Google Scholar] that causes constitutive elevation of resting [Ca2+]mit. Recently, homozygous deletion of exon 1 of MICU1 in children affected by fatigue and lethargy has been reported to induce a strong reduction of mitochondrial Ca2+ uptake. However, a concomitant decrease in pyruvate dehydrogenase (PDH) phosphorylation, which is regulated by the Ca2+-dependent PDH phosphatase, was detected [43Lewis-Smith D. et al.Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood.Neurol. Genet. 2016; 2: e59Crossref PubMed Scopus (43) Google Scholar], suggesting th" @default.
• W2527503499 created "2016-10-07" @default.
• W2527503499 creator A5021079841 @default.
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• W2527503499 date "2016-12-01" @default.
• W2527503499 modified "2023-10-06" @default.
• W2527503499 title "Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes" @default.
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