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https://www.readbyqxmd.com/read/28916471/the-pyk2-mcu-pathway-in-the-rat-middle-cerebral-artery-occlusion-model-of-ischemic-stroke
#1
Kun Zhang, Jiajia Yan, Liang Wang, Xinying Tian, Tong Zhang, Li Guo, Bin Li, Wang Wang, Xiaoyun Liu
Mitochondrial dysfunction caused by Ca(2+) overload plays an important role in ischemia-induced brain damage. Mitochondrial calcium uniporter (MCU), located on the mitochondrial inner membrane, is the major channel responsible for mitochondrial Ca(2+) uptake. Activated proline-rich tyrosine kinase 2 (Pyk2) can directly phosphorylate MCU, which enhances mitochondrial Ca(2+) uptake in cardiomyocytes. It has been suggested that the Pyk2/MCU pathway may be a novel therapeutic target in stress-induced cellular apoptosis...
September 12, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28882140/role-of-mitochondrial-dysfunction-and-dysregulation-of-ca-2-homeostasis-in-the-pathophysiology-of-insulin-resistance-and-type-2-diabetes
#2
REVIEW
Chih-Hao Wang, Yau-Huei Wei
Metabolic diseases such as obesity, type 2 diabetes (T2D) and insulin resistance have attracted great attention from biomedical researchers and clinicians because of the astonishing increase in its prevalence. Decrease in the capacity of oxidative metabolism and mitochondrial dysfunction are a major contributor to the development of these metabolic disorders. Recent studies indicate that alteration of intracellular Ca(2+) levels and downstream Ca(2+)-dependent signaling pathways appear to modulate gene transcription and the activities of many enzymes involved in cellular metabolism...
September 7, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28874604/mitochondrial-redox-signaling-enables-repair-of-injured-skeletal-muscle-cells
#3
Adam Horn, Jack H Van der Meulen, Aurelia Defour, Marshall Hogarth, Sen Chandra Sreetama, Aaron Reed, Luana Scheffer, Navdeep S Chandel, Jyoti K Jaiswal
Strain and physical trauma to mechanically active cells, such as skeletal muscle myofibers, injures their plasma membranes, and mitochondrial function is required for their repair. We found that mitochondrial function was also needed for plasma membrane repair in myoblasts as well as nonmuscle cells, which depended on mitochondrial uptake of calcium through the mitochondrial calcium uniporter (MCU). Calcium uptake transiently increased the mitochondrial production of reactive oxygen species (ROS), which locally activated the guanosine triphosphatase (GTPase) RhoA, triggering F-actin accumulation at the site of injury and facilitating membrane repair...
September 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/28867646/the-mcu-complex-in-cell-death
#4
REVIEW
Elisa Penna, Javier Espino, Diego De Stefani, Rosario Rizzuto
During the 60s, the notion that positively charged Ca(2+) ions are rapidly accumulated in energized mitochondria has been first established. In the following decades, mitochondrial Ca(2+) homeostasis was shown to control cell metabolism, cell survival and other cell-specific functions through different mechanism. However, the molecular identity of the molecules controlling this process remained a mystery until just few years ago, when both mitochondrial Ca(2+) uptake and release systems were genetically dissected...
August 25, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28838811/mitochondrial-calcium-imbalance-in-parkinson-s-disease
#5
REVIEW
Marthe H R Ludtmann, Andrey Y Abramov
Multiple factors are involved in the mechanism(s) of neuronal loss in neurodegenerative disorders whilst mitochondria are thought to play a central role in neurodegeneration of Parkinson's disease. Mitochondria are vital to cellular functions by supplying energy in form of ATP and affect cell physiology via calcium, ROS and signalling proteins. Changes in mitochondrial calcium homeostasis and ROS overproduction can induce cell death by triggering mitochondrial permeability transition pore opening. One of the major triggers for PTP is mitochondrial calcium overload...
August 26, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28820965/systematic-identification-of-mcu-modulators-by-orthogonal-interspecies-chemical-screening
#6
Daniela M Arduino, Jennifer Wettmarshausen, Horia Vais, Paloma Navas-Navarro, Yiming Cheng, Anja Leimpek, Zhongming Ma, Alba Delrio-Lorenzo, Andrea Giordano, Cecilia Garcia-Perez, Guillaume Médard, Bernhard Kuster, Javier García-Sancho, Dejana Mokranjac, J Kevin Foskett, M Teresa Alonso, Fabiana Perocchi
The mitochondrial calcium uniporter complex is essential for calcium (Ca(2+)) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca(2+) signal transduction. Despite its involvement in several human diseases, we currently lack pharmacological agents for targeting uniporter activity. Here we introduce a high-throughput assay that selects for human MCU-specific small-molecule modulators in primary drug screens. Using isolated yeast mitochondria, reconstituted with human MCU, its essential regulator EMRE, and aequorin, and exploiting a D-lactate- and mannitol/sucrose-based bioenergetic shunt that greatly minimizes false-positive hits, we identify mitoxantrone out of more than 600 clinically approved drugs as a direct selective inhibitor of human MCU...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28790027/increased-mitochondrial-calcium-uniporter-in-adipocytes-underlies-mitochondrial-alterations-associated-with-insulin-resistance
#7
Lauren E Wright, Denis Vecellio Reane, Gabriella Milan, Anna Terrin, Giorgia di Bello, Anna Belligoli, Marta Sanna, Mirto Foletto, Francesca Favaretto, Anna Raffaello, Cristina Mammucari, Donato Nitti, Roberto Vettor, Rosario Rizzuto
Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the Mitochondrial Calcium Uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca(2+) in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analysed from several models of obese and diabetic rodents and in obese patients, as well as in vitro insulin-resistant adipocytes...
August 8, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28740830/structure-activity-regulation-and-role-of-the-mitochondrial-calcium-uniporter-in-health-and-disease
#8
REVIEW
Cristina Mammucari, Gaia Gherardi, Rosario Rizzuto
Mitochondrial Ca(2+) uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca(2+) signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca(2+) signaling in cell and tissue homeostasis...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28732507/long-noncoding-rna-expression-profiles-in-sub-lethal-heat-treated-hepatoma-carcinoma-cells
#9
Qingsong Deng, Shihan Chen, Chunchuan Fu, Jiayun Jiang, Mengda Zou, Yunhua Tan, Xiaofei Wang, Feng Xia, Kai Feng, Kuansheng Ma, Ping Bie
BACKGROUND: Sub-lethal heat treatment characterizes a transition zone of radiofrequency ablation (RFA) which explains hepatocellular carcinoma (HCC) residual cancer occurrence in this area after RFA treatment. The biochemistry of residual cancer cell recurrence is poorly understood, but long noncoding RNAs (lncRNAs) may have aberrant expression that is associated with diverse cancers. Thus, we measured lncRNA gene expression in sub-lethally heat-treated HCC cells using microarray. METHOD: Differentially expressed lncRNA and mRNA were measured with an Agilent Human lncRNA + mRNA Array V4...
July 21, 2017: World Journal of Surgical Oncology
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
#10
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...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28725491/ds16570511-is-a-small-molecule-inhibitor-of-the-mitochondrial-calcium-uniporter
#11
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
#12
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/28650465/mcu-dependent-mitochondrial-ca-2-inhibits-nad-sirt3-sod2-pathway-to-promote-ros-production-and-metastasis-of-hcc-cells
#13
T Ren, H Zhang, J Wang, J Zhu, M Jin, Y Wu, X Guo, L Ji, Q Huang, H Zhang, H Yang, J Xing
Mitochondrial Ca(2+) signaling, which is strongly dependent on the mitochondrial Ca(2+) uniporter (MCU) complex, has a series of key roles in physiopathological processes, including energy metabolism, reactive oxygen species (ROS) production and cell apoptosis. However, a mechanistic understanding of how the mitochondrial Ca(2+) signaling is remodeled and its functional roles remains greatly limited in cancers, especially in hepatocellular carcinoma. Here we demonstrated that the MCU complex was dysregulated in hepatocellular carcinoma (HCC) cells and significantly correlated with metastasis and poor prognosis of HCC patients...
June 26, 2017: Oncogene
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
#14
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/28578342/astragaloside-iv-protects-against-heat-induced-apoptosis-by-inhibiting-excessive-activation-of-mitochondrial-ca2-uniporter
#15
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/28560396/mitochondrial-ca2-removal-amplifies-trail-cytotoxicity-toward-apoptosis-resistant-tumor-cells-via-promotion-of-multiple-cell-death-modalities
#16
Natsuhiko Takata, Yohei Ohshima, Miki Suzuki-Karasaki, Yukihiro Yoshida, Yasuaki Tokuhashi, Yoshihiro Suzuki-Karasaki
Ca2+ has emerged as a new target for cancer treatment since tumor-specific traits in Ca2+ dynamics contributes to tumorigenesis, malignant phenotypes, drug resistance, and survival in different tumor types. However, Ca2+ has a dual (pro-death and pro-survival) function in tumor cells depending on the experimental conditions. Therefore, it is necessary to minimize the onset of the pro-survival Ca2+ signals caused by the therapy. For this purpose, a better understanding of pro-survival Ca2+ pathways in cancer cells is critical...
May 25, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28495532/new-insights-into-the-role-of-mitochondrial-calcium-homeostasis-in-cell-migration
#17
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
#18
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/28438761/improved-skeletal-muscle-ca-2-regulation-in-vivo-following-contractions-in-mice-overexpressing-pgc-1%C3%AE
#19
Hiroaki Eshima, Shinji Miura, Nanami Senoo, Koji Hatakeyama, David C Poole, Yutaka Kano
In skeletal muscle, resting intracellular Ca(2+) concentration ([Ca(2+)]i) homeostasis is exquisitely regulated by Ca(2+) transport across the sarcolemmal, mitochondrial, and sarcoplasmic reticulum (SR) membranes. Of these three systems, the relative importance of the mitochondria in [Ca(2+)]i regulation remains poorly understood in in vivo skeletal muscle. We tested the hypothesis that the capacity for Ca(2+) uptake by mitochondria is a primary factor in determining [Ca(2+)]i regulation in muscle at rest and following contractions...
June 1, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28396416/proteolytic-control-of-the-mitochondrial-calcium-uniporter-complex
#20
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
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