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Mitochondrial calcium uniporter

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https://www.readbyqxmd.com/read/28726639/mitochondrial-calcium-uniporter-in-drosophila-transfers-calcium-between-the-endoplasmic-reticulum-and-mitochondria-in-oxidative-stress-induced-cell-death
#1
Sekyu Choi, Xianglan Quan, Sunhoe Bang, Heesuk Yoo, Jiyoung Kim, Jiwon Park, Kyu-Sang Park, Jongkyeong Chung
Mitochondrial calcium plays critical roles in diverse cellular processes ranging from energy metabolism to cell death. Previous studies have demonstrated that mitochondrial calcium uptake is mainly mediated by the mitochondrial calcium uniporter (MCU) complex. However, the roles of the MCU complex in calcium transport, signaling, and dysregulation by oxidative stress still remain unclear. Here, we confirmed that Drosophila MCU contains evolutionarily conserved structures and requires essential MCU regulator (EMRE) for its calcium channel activities...
July 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28725491/ds16570511-is-a-small-molecule-inhibitor-of-the-mitochondrial-calcium-uniporter
#2
Naohiro Kon, Michiko Murakoshi, Aya Isobe, Katsuji Kagechika, Naoki Miyoshi, Takahiro Nagayama
In cardiac myocytes, regulation of mitochondrial Ca(2+) is important for cellular signaling and cardiac contraction. Ca(2+) entry into the mitochondria is mediated by a highly selective Ca(2+) channel called the mitochondrial calcium uniporter, which consists of a pore-forming subunit MCU and regulatory subunits such as MICU1. Although pharmacological regulation of the mitochondrial Ca(2+) influx is a promising approach to controlling the cellular functions, a cell-permeable and specific inhibitor of the mitochondrial calcium uniporter has not yet been developed...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28698627/the-energy-disruptor-metformin-targets-mitochondrial-integrity-via-modification-of-calcium-flux-in-cancer-cells
#3
Camille Loubiere, Stephan Clavel, Jerome Gilleron, Rania Harisseh, Jeremy Fauconnier, Issam Ben-Sahra, Lisa Kaminski, Kathiane Laurent, Stephanie Herkenne, Sandra Lacas-Gervais, Damien Ambrosetti, Damien Alcor, Stephane Rocchi, Mireille Cormont, Jean-François Michiels, Bernard Mari, Nathalie M Mazure, Luca Scorrano, Alain Lacampagne, Abdallah Gharib, Jean-François Tanti, Frederic Bost
Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU)...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646724/zinc-and-calcium-alter-the-relationship-between-mitochondrial-respiration-ros-and-membrane-potential-in-rainbow-trout-oncorhynchus-mykiss-liver-mitochondria
#4
Mahmoud S Sharaf, Don Stevens, Collins Kamunde
At excess levels, zinc (Zn) disrupts mitochondrial functional integrity and induces oxidative stress in aquatic organisms. Although much is known about the modulation of Zn toxicity by calcium (Ca) in fish, their interactions at the mitochondrial level have scarcely been investigated. Here we assessed the individual and combined effects of Zn and Ca on the relationship between mitochondrial respiration, ROS and membrane potential (ΔΨmt) in rainbow trout liver mitochondria. We tested if cation uptake through the mitochondrial calcium uniporter (MCU) is a prerequisite for Zn- and/or Ca-induced alteration of mitochondrial function...
August 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/28615291/high-affinity-cooperative-ca-2-binding-by-micu1-micu2-serves-as-an-on-off-switch-for-the%C3%A2-uniporter
#5
Kimberli J Kamer, Zenon Grabarek, Vamsi K Mootha
The mitochondrial calcium uniporter is a Ca(2+)-activated Ca(2+) channel that is essential for dynamic modulation of mitochondrial function in response to cellular Ca(2+) signals. It is regulated by two paralogous EF-hand proteins-MICU1 and MICU2, but the mechanism is unknown. Here, we demonstrate that both MICU1 and MICU2 are stabilized by Ca(2+) We reconstitute the MICU1-MICU2 heterodimer and demonstrate that it binds Ca(2+) cooperatively with high affinity. We discover that both MICU1 and MICU2 exhibit affinity for the mitochondria-specific lipid cardiolipin...
June 14, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28578342/astragaloside-iv-protects-against-heat-induced-apoptosis-by-inhibiting-excessive-activation-of-mitochondrial-ca2-uniporter
#6
Zhiwei Dong, Chen Zhang, Yajie Chen, Yu Chen, Zhiqiang Yuan, Yizhi Peng, Tongtong Cao
BACKGROUND: Heat causes airway damage during inhalation injury because of bronchial epithelial cell damage. Accumulating evidence shows that mitochondrial uniporter (MCU) is involved in cell damage. We investigated the MCU activity after heat treatment and assessed whether Astragaloside-IV (AS-IV) suppresses heat-induced apoptosis in bronchial epithelial cells by inhibiting the activation of the mitochondrial Ca2+ uniporter (MCU), mitochondrial depolarisation and reactive oxygen species (ROS) production...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28551788/functional-role-of-mitochondria-in-arrhythmogenesis
#7
Jessica Gambardella, Daniela Sorriento, Michele Ciccarelli, Carmine Del Giudice, Antonella Fiordelisi, Luigi Napolitano, Bruno Trimarco, Guido Iaccarino, Gaetano Santulli
Growing evidence indicate that mitochondria play a functional role in arrhythmogenesis. We report here the molecular mechanisms underlying the action of these highly dynamic organelles in the regulation of cell metabolism, action potential and, overall, heart excitability. In particular, we examine the role of cardiac mitochondria in linking metabolism and cell excitability. The importance of the main mitochondrial channels is evaluated as well, including the recently identified calcium uniporter. Promises and pitfalls of potential therapeutic strategies targeting mitochondrial pathways are also assessed...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28551786/mitochondrial-bioenergetics-during-ischemia-and-reperfusion
#8
Alicia E Consolini, María I Ragone, Patricia Bonazzola, Germán A Colareda
During ischemia and reperfusion (I/R) mitochondria suffer a deficiency to supply the cardiomyocyte with chemical energy, but also contribute to the cytosolic ionic alterations especially of Ca(2+). Their free calcium concentration ([Ca(2+)]m) mainly depends on mitochondrial entrance through the uniporter (UCam) and extrusion in exchange with Na(+) (mNCX) driven by the electrochemical gradient (ΔΨm). Cardiac energetic is frequently estimated by the oxygen consumption, which determines metabolism coupled to ATP production and to the maintaining of ΔΨm...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28551781/the-in-vivo-biology-of-the-mitochondrial-calcium-uniporter
#9
Julia C Liu, Randi J Parks, Jie Liu, Justin Stares, Ilsa I Rovira, Elizabeth Murphy, Toren Finkel
The identification of the molecular composition of the mitochondrial calcium uniporter has allowed for the genetic manipulation of its components and the creation of various in vivo genetic models. Here, we review the initial attempts to modulate the expression of components of the calcium uniporter in a range of organisms from plants to mammals. This analysis has confirmed the strict requirement for the uniporter for in vivo mitochondrial calcium uptake and for maintaining mitochondrial calcium homeostasis...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28516062/endoplasmic-reticulum-mitochondrial-ca-2-fluxes-underlying-cancer-cell-survival
#10
REVIEW
Hristina Ivanova, Martijn Kerkhofs, Rita M La Rovere, Geert Bultynck
Calcium ions (Ca(2+)) are crucial, ubiquitous, intracellular second messengers required for functional mitochondrial metabolism during uncontrolled proliferation of cancer cells. The mitochondria and the endoplasmic reticulum (ER) are connected via "mitochondria-associated ER membranes" (MAMs) where ER-mitochondria Ca(2+) transfer occurs, impacting the mitochondrial biology related to several aspects of cellular survival, autophagy, metabolism, cell death sensitivity, and metastasis, all cancer hallmarks. Cancer cells appear addicted to these constitutive ER-mitochondrial Ca(2+) fluxes for their survival, since they drive the tricarboxylic acid cycle and the production of mitochondrial substrates needed for nucleoside synthesis and proper cell cycle progression...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28495532/new-insights-into-the-role-of-mitochondrial-calcium-homeostasis-in-cell-migration
#11
Vincent Paupe, Julien Prudent
Mitochondria are dynamic organelles involved in numerous physiological functions. Beyond their function in ATP production, mitochondria regulate cell death, reactive oxygen species (ROS) generation, immunity and metabolism. Mitochondria also play a key role in the buffering of cytosolic calcium, and calcium transported into the matrix regulates mitochondrial metabolism. Recently, the identification of the mitochondrial calcium uniporter (MCU) and associated regulators has allowed the characterization of new physiological roles for calcium in both mitochondrial and cellular homeostasis...
May 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28487431/different-roles-of-mitochondrial-calcium-uniporter-complex-subunits-in-growth-and-infectivity-of-trypanosoma-cruzi
#12
Miguel A Chiurillo, Noelia Lander, Mayara S Bertolini, Melissa Storey, Anibal E Vercesi, Roberto Docampo
Trypanosoma cruzi is the agent of Chagas disease, and the finding that this parasite possesses a mitochondrial calcium uniporter (TcMCU) with characteristics similar to that of mammalian mitochondria was fundamental for the discovery of the molecular nature of MCU in eukaryotes. We report here that ablation of TcMCU, or its paralog TcMCUb, by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 led to a marked decrease in mitochondrial Ca(2+) uptake without affecting the membrane potential of these cells, whereas overexpression of each gene caused a significant increase in the ability of mitochondria to accumulate Ca(2+) While TcMCU-knockout (KO) epimastigotes were viable and able to differentiate into trypomastigotes, infect host cells, and replicate normally, ablation of TcMCUb resulted in epimastigotes having an important growth defect, lower rates of respiration and metacyclogenesis, more pronounced autophagy changes under starvation, and significantly reduced infectivity...
May 9, 2017: MBio
https://www.readbyqxmd.com/read/28396416/proteolytic-control-of-the-mitochondrial-calcium-uniporter-complex
#13
Chen-Wei Tsai, Yujiao Wu, Ping-Chieh Pao, Charles B Phillips, Carole Williams, Christopher Miller, Matthew Ranaghan, Ming-Feng Tsai
The mitochondrial calcium uniporter is a Ca(2+)-activated Ca(2+) channel complex mediating mitochondrial Ca(2+) uptake, a process crucial for Ca(2+) signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-pass membrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28388446/phosphorylation-of-dynamin-related-protein-1-at-ser616-regulates-mitochondrial-fission-and-is-involved-in-mitochondrial-calcium-uniporter-mediated-neutrophil-polarization-and-chemotaxis
#14
Xianchong Zheng, Mimi Chen, Xiaojing Meng, Xinwei Chu, Chunqing Cai, Fei Zou
During an inflammatory response, polarization of neutrophils is necessary for effective chemotaxis and bacterial endocytosis. Ca(2+) uptake into mitochondria through the mitochondrial calcium uniporter (MCU) is crucial for cell metabolism, signaling and survival; however, the physiological role of MCU in human neutrophils remains unclear. Here we show that MCU is vital for the polarization and chemotaxis of neutrophils. Activation of MCU by spermine promotes neutrophil polarization and chemotaxis, whereas inhibition of MCU by Ru360 blunts both processes...
April 4, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28351840/macrophages-utilize-the-mitochondrial-calcium-uniporter-for-profibrotic-polarization
#15
Linlin Gu, Jennifer L Larson-Casey, A Brent Carter
Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca(2+) levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca(2+) compared with normal patients...
July 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28337252/small-interfering-rna-targeting-mitochondrial-calcium-uniporter-improves-cardiomyocyte-cell-viability-in-hypoxia-reoxygenation-injury-by-reducing-calcium-overload
#16
Yuriana Oropeza-Almazán, Eduardo Vázquez-Garza, Héctor Chapoy-Villanueva, Guillermo Torre-Amione, Gerardo García-Rivas
Intracellular Ca(2+) mishandling is an underlying mechanism in hypoxia/reoxygenation (H/R) injury that results in mitochondrial dysfunction and cardiomyocytes death. These events are mediated by mitochondrial Ca(2+) (mCa(2+)) overload that is facilitated by the mitochondrial calcium uniporter (MCU) channel. Along this line, we evaluated the effect of siRNA-targeting MCU in cardiomyocytes subjected to H/R injury. First, cardiomyocytes treated with siRNA demonstrated a reduction of MCU expression by 67%, which resulted in significant decrease in mitochondrial Ca(2+) transport...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28325874/ion-and-inhibitor-binding-of-the-double-ring-ion-selectivity-filter-of-the-mitochondrial-calcium-uniporter
#17
Chan Cao, Shuqing Wang, Tanxing Cui, Xun-Cheng Su, James J Chou
The calcium (Ca(2+)) uniporter of mitochondria is a holocomplex consisting of the Ca(2+)-conducting channel, known as mitochondrial calcium uniporter (MCU), and several accessory and regulatory components. A previous electrophysiology study found that the uniporter has high Ca(2+) selectivity and conductance and this depends critically on the conserved amino acid sequence motif, DXXE (Asp-X-X-Glu) of MCU. A recent NMR structure of the MCU channel from Caenorhabditis elegans revealed that the DXXE forms two parallel carboxylate rings at the channel entrance that seem to serve as the ion selectivity filter, although direct ion interaction of this structural motif has not been addressed...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28306510/redox-control-of-mitochondrial-calcium-uptake
#18
Nicolas Demaurex, Manon Rosselin
Dong et al. (2017) establish how the mitochondrial Ca(2+) uniporter (MCU) integrates Ca(2+) and oxidative stress signals by identifying a cysteine residue that controls MCU channel activity, a mechanism causing mitochondrial Ca(2+) overload and cell death during oxidative stress.
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28280417/hydrogen-peroxide-attenuates-refilling-of-intracellular-calcium-store-in-mouse-pancreatic-acinar-cells
#19
Mi Na Yoon, Dong Kwan Kim, Se Hoon Kim, Hyung Seo Park
Intracellular calcium (Ca(2+)) oscillation is an initial event in digestive enzyme secretion of pancreatic acinar cells. Reactive oxygen species are known to be associated with a variety of oxidative stress-induced cellular disorders including pancreatitis. In this study, we investigated the effect of hydrogen peroxide (H2O2) on intracellular Ca(2+) accumulation in mouse pancreatic acinar cells. Perfusion of H2O2 at 300 µM resulted in additional elevation of intracellular Ca(2+) levels and termination of oscillatory Ca(2+) signals induced by carbamylcholine (CCh) in the presence of normal extracellular Ca(2+)...
March 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28273446/tissue-specific-mitochondrial-decoding-of-cytoplasmic-ca-2-signals-is-controlled-by-the-stoichiometry-of-micu1-2-and-mcu
#20
Melanie Paillard, György Csordás, Gergö Szanda, Tünde Golenár, Valentina Debattisti, Adam Bartok, Nadan Wang, Cynthia Moffat, Erin L Seifert, András Spät, György Hajnóczky
Mitochondrial Ca(2+) uptake through the Ca(2+) uniporter supports cell functions, including oxidative metabolism, while meeting tissue-specific calcium signaling patterns and energy needs. The molecular mechanisms underlying tissue-specific control of the uniporter are unknown. Here, we investigated a possible role for tissue-specific stoichiometry between the Ca(2+)-sensing regulators (MICUs) and pore unit (MCU) of the uniporter. Low MICU1:MCU protein ratio lowered the [Ca(2+)] threshold for Ca(2+) uptake and activation of oxidative metabolism but decreased the cooperativity of uniporter activation in heart and skeletal muscle compared to liver...
March 7, 2017: Cell Reports
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