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Journal ArticleDOI: 10.1016/J.TCB.2021.02.003

Balancing ER-Mitochondrial Ca2+ Fluxes in Health and Disease

04 Mar 2021-Trends in Cell Biology (Elsevier)-Vol. 31, Iss: 7, pp 598-612
Abstract: Organelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca2+-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca2+-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca2+ signals from the ER toward mitochondria. This provides tight control of mitochondrial functions at the microdomain level. Here, we discuss how ER–mitochondrial Ca2+ transfers support cell function and how their dysregulation underlies, drives, or contributes to pathogenesis and pathophysiology, with a major focus on cancer and neurodegeneration but also with attention to other diseases such as diabetes and rare genetic diseases.

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Topics: Cellular homeostasis (56%), Endoplasmic reticulum (53%), Mitochondrion (52%) ... show more

14 results found

Journal ArticleDOI: 10.1016/J.BBAMCR.2021.119020
Abstract: Inside cells, the endoplasmic reticulum (ER) forms the largest Ca2+ store Ca2+ is actively pumped by the SERCA pumps in the ER, where intraluminal Ca2+-binding proteins enable the accumulation of large amount of Ca2+ IP3 receptors and the ryanodine receptors mediate the release of Ca2+ in a controlled way, thereby evoking complex spatio-temporal signals in the cell The steady state Ca2+ concentration in the ER of about 500 μM results from the balance between SERCA-mediated Ca2+ uptake and the passive leakage of Ca2+ The passive Ca2+ leak from the ER is often ignored, but can play an important physiological role, depending on the cellular context Moreover, excessive Ca2+ leakage significantly lowers the amount of Ca2+ stored in the ER compared to normal conditions, thereby limiting the possibility to evoke Ca2+ signals and/or causing ER stress, leading to pathological consequences The so-called Ca2+-leak channels responsible for Ca2+ leakage from the ER are however still not well understood, despite over 20 different proteins have been proposed to contribute to it This review has the aim to critically evaluate the available evidence about the various channels potentially involved and to draw conclusions about their relative importance

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Topics: SERCA (55%), Unfolded protein response (52%), Endoplasmic reticulum (51%) ... show more

6 Citations

Open accessJournal ArticleDOI: 10.1016/J.TCB.2021.06.010
Abstract: Organelles are critical structures in mediating the assembly and activation of inflammasomes in mammalian cells, resulting in inflammation and cell death. Assembly of inflammasomes can occur at the mitochondria, endoplasmic reticulum, nucleus, trans-Golgi network, or pathogen surface, facilitated by the overarching architecture of the cytoskeleton. NLRP3 and Pyrin inflammasome sensors may form smaller speckles and converge on a single larger speck at the microtubule-organizing center (MTOC). This signaling hub activates multiple mammalian inflammatory and apoptotic caspases, cytokine substrates, the pore-forming protein gasdermin D, and the plasma membrane rupture protein ninjurin-1 (NINJ1), allowing pyroptosis, cellular disintegration, and inflammation to ensue. In this review, we highlight the role of mammalian cell types and organellar architectures in executing inflammasome responses.

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Topics: Inflammasome (59%), Pyroptosis (56%), Pyrin domain (51%) ... show more

3 Citations

Journal ArticleDOI: 10.1016/J.BBAMCR.2021.119099
Abstract: Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca2+ release channels activated by a ligand (IP3). IP3R-mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca2+ transfer and senescence. Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.

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Topics: Senescence (57%), Mitochondrion (53%), Endoplasmic reticulum (52%) ... show more

2 Citations

Journal ArticleDOI: 10.1016/J.BBAMCR.2021.118997
Abstract: The family of B-cell lymphoma-2 (Bcl-2) proteins exerts key functions in cellular health. Bcl-2 primarily acts in mitochondria where it controls the initiation of apoptosis. However, during the last decades, it has become clear that this family of proteins is also involved in controlling intracellular Ca2+ signaling, a critical process for the function of most cell types, including neurons. Several anti- and pro-apoptotic Bcl-2 family members are expressed in neurons and impact neuronal function. Importantly, expression levels of neuronal Bcl-2 proteins are affected by age. In this review, we focus on the emerging roles of Bcl-2 proteins in neuronal cells. Specifically, we discuss how their dysregulation contributes to the onset, development, and progression of neurodegeneration in the context of Alzheimer's disease (AD). Aberrant Ca2+ signaling plays an important role in the pathogenesis of AD, and we propose that dysregulation of the Bcl-2-Ca2+ signaling axis may contribute to the progression of AD and that herein, Bcl-2 may constitute a potential therapeutic target for the treatment of AD.

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Topics: Neurodegeneration (54%)

1 Citations

Open accessJournal ArticleDOI: 10.1186/S12964-021-00762-7
Fanyun Kong1, Fulong Zhang, Xiangye Liu1, Suping Qin1  +6 moreInstitutions (1)
Abstract: As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. Video Abstract.

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Topics: Hepatitis B virus (59%), Calcium signaling (55%), Hepatitis (51%) ... show more

1 Citations


113 results found

Journal ArticleDOI: 10.1126/SCIENCE.1077209
10 Jan 2003-Science
Abstract: The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.

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Topics: PARK7 (60%), Parkinsonism (59%), Neurodegeneration (54%) ... show more

2,478 Citations

Journal ArticleDOI: 10.1038/NATURE07534
04 Dec 2008-Nature
Abstract: Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.

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Topics: mitochondrial fusion (56%), Endoplasmic reticulum (55%), MFN2 (54%) ... show more

1,795 Citations

Open accessJournal ArticleDOI: 10.1016/J.CELL.2007.08.036
Teruo Hayashi1, Tsung-Ping Su1Institutions (1)
02 Nov 2007-Cell
Abstract: Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.

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Topics: Unfolded protein response (60%), Endoplasmic reticulum (54%), Sigma-1 receptor (54%) ... show more

1,255 Citations

Journal ArticleDOI: 10.1038/NRM3412
Abstract: During the past two decades calcium (Ca(2+)) accumulation in energized mitochondria has emerged as a biological process of utmost physiological relevance. Mitochondrial Ca(2+) uptake was shown to control intracellular Ca(2+) signalling, cell metabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca(2+) levels and regulating mitochondrial effectors. Recently, the identity of mitochondrial Ca(2+) transporters has been revealed, opening new perspectives for investigation and molecular intervention.

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Topics: Mitochondrial calcium uptake (66%), Calcium signaling (53%), Mitochondrion (53%) ... show more

1,166 Citations

Open accessJournal ArticleDOI: 10.1083/JCB.200608073
Abstract: The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca2+, and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum Ca2+-release channel inositol 1,4,5-trisphosphate receptor (IP3R) through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was shown by the recombinant expression of the ligand-binding domain of the IP3R on the ER or mitochondrial surface, which directly enhanced Ca2+ accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP3R and the mitochondrial Ca2+ uptake machinery. Because organelle Ca2+ homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis.

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Topics: Endoplasmic reticulum (65%), STIM1 (65%), VDAC1 (64%) ... show more

953 Citations

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