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Mitochondrial calcium uniporter

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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/28866381/cytochrome-c-oxidase-inhibition-by-calcium-at-physiological-ionic-composition-of-the-medium-implications-for-physiological-significance-of-the-effect
#4
Tatiana V Vygodina, Elizaveta Mukhaleva, Natalia V Azarkina, Alexander A Konstantinov
Cytochrome c oxidase (CcO) from mammalian mitochondria binds Ca(2+) and Na(+) in a special cation binding site. Binding of Ca(2+) brings about partial inhibition of the enzyme while Na(+) competes with Ca(2+) for the binding site and protects the enzyme from the inhibition [Vygodina, T., Kirichenko, A. and Konstantinov, A.A. (2013). Direct Regulation of Cytochrome c Oxidase by Calcium Ions. PLoS One 8(9): e74436]. In the original studies, the inhibition was found to depend significantly on the ionic composition of the buffer...
August 31, 2017: Biochimica et Biophysica Acta
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/28777009/importance-of-mitochondrial-calcium-uniporter-in-high-glucose-induced-endothelial-cell-dysfunction
#8
Wei Chen, Jie Yang, Shuhua Chen, Hong Xiang, Hengdao Liu, Dan Lin, Shaoli Zhao, Hui Peng, Pan Chen, Alex F Chen, Hongwei Lu
OBJECTIVE: Mitochondrial Ca(2+) overload is implicated in hyperglycaemia-induced endothelial cell dysfunction, but the key molecular events responsible remain unclear. We examined the involvement of mitochondrial calcium uniporter, which mediates mitochondrial Ca(2+) uptake, in endothelial cell dysfunction resulting from high-glucose treatment. METHODS: Human umbilical vein endothelial cells were exposed to various glucose concentrations and to high glucose (30 mM) following mitochondrial calcium uniporter inhibition or activation with ruthenium red and spermine, respectively...
August 1, 2017: Diabetes & Vascular Disease Research
https://www.readbyqxmd.com/read/28761044/resveratrol-reverses-the-warburg-effect-by-targeting-the-pyruvate-dehydrogenase-complex-in-colon-cancer-cells
#9
Elise Saunier, Samantha Antonio, Anne Regazzetti, Nicolas Auzeil, Olivier Laprévote, Jerry W Shay, Xavier Coumoul, Robert Barouki, Chantal Benelli, Laurence Huc, Sylvie Bortoli
Resveratrol (RES), a polyphenol found in natural foods, displays anti-oxidant, anti-inflammatory and anti-proliferative properties potentially beneficial in cancers, in particular in the prevention of tumor growth. However, the rapid metabolism of resveratrol strongly limits its bioavailability. The molecular mechanisms sustaining the potential biological activity of low doses of resveratrol has not been extensively studied and, thus, needs better characterization. Here, we show that resveratrol (10 µM, 48 hr) induces both a cell growth arrest and a metabolic reprogramming in colon cancer cells...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28740830/structure-activity-regulation-and-role-of-the-mitochondrial-calcium-uniporter-in-health-and-disease
#10
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/28726639/mitochondrial-calcium-uniporter-in-drosophila-transfers-calcium-between-the-endoplasmic-reticulum-and-mitochondria-in-oxidative-stress-induced-cell-death
#11
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
#12
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
#13
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
#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/28615291/high-affinity-cooperative-ca-2-binding-by-micu1-micu2-serves-as-an-on-off-switch-for-the%C3%A2-uniporter
#15
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...
August 2017: EMBO Reports
https://www.readbyqxmd.com/read/28578342/astragaloside-iv-protects-against-heat-induced-apoptosis-by-inhibiting-excessive-activation-of-mitochondrial-ca2-uniporter
#16
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
#17
REVIEW
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
#18
REVIEW
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
#19
REVIEW
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
#20
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
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