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Mitochondrial calcium uniporter

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https://www.readbyqxmd.com/read/27924224/micu1-may-be-a-promising-intervention-target-for-gut-derived-sepsis-induced-by-intra-abdominal-hypertension
#1
Yuxin Leng, Qinggang Ge, Zhiling Zhao, Kun Wang, Gaiqi Yao
Intra-abdominal hypertension (IAH) is a common and serious complication in critically ill patients, for which there is no targeted therapy. IAH-induced dysfunction of intestinal barriers is closely associated with oxidative imbalances, which are considered to provide a pathophysiological basis for subsequent gut-derived sepsis. However, the upstream mechanism that produces oxidative damage during IAH remains unknown. It is not clear whether 'mitochondrial Ca(2+) uptake 1' (MICU1, the key protein regulating the oxidative process) is involved in preventing Ca(2+)m (mitochondrial Ca(2+)) overload...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27924223/mitochondrial-permeability-transition-pore-induction-is-linked-to-formation-of-the-complex-of-atpase-c-subunit-polyhydroxybutyrate-and-inorganic-polyphosphate
#2
P A Elustondo, M Nichols, A Negoda, A Thirumaran, E Zakharian, G S Robertson, E V Pavlov
Mitochondrial permeability transition pore (mPTP) opening allows free movement of ions and small molecules leading to mitochondrial membrane depolarization and ATP depletion that triggers cell death. A multi-protein complex of the mitochondrial ATP synthase has an essential role in mPTP. However, the molecular identity of the central 'pore' part of mPTP complex is not known. A highly purified fraction of mammalian mitochondria containing C-subunit of ATPase (C-subunit), calcium, inorganic polyphosphate (polyP) and polyhydroxybutyrate (PHB) forms ion channels with properties that resemble the native mPTP...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27923677/intact-mitochondrial-ca-2-uniport-is-essential-for-agonist-induced-activation-of-endothelial-nitric-oxide-synthase-enos
#3
Suphachai Charoensin, Emrah Eroglu, Marissa Opelt, Helmut Bischof, Corina T Madreiter-Sokolowski, Andrijana Kirsch, Maria R Depaoli, Saša Frank, Astrid Schrammel, Bernd Mayer, Markus Waldeck-Weiermair, Wolfgang F Graier, Roland Malli
Mitochondrial Ca(2+) uptake regulates diverse endothelial cell functions and has also been related to nitric oxide (NO(•)) production. However, it is not entirely clear if the organelles support or counteract NO(•) biosynthesis by taking up Ca(2+). The objective of this study was to verify whether or not mitochondrial Ca(2+) uptake influences Ca(2+)-triggered NO(•) generation by endothelial NO(•) synthase (eNOS) in an immortalized endothelial cell line (EA.hy926), respective primary human umbilical vein endothelial cells (HUVECs) and eNOS-RFP (red fluorescent protein) expressing human embryonic kidney (HEK293) cells...
December 3, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27909264/global-ablation-of-the-mitochondrial-calcium-uniporter-increases-glycolysis-in-cortical-neurons-subjected-to-energetic-stressors
#4
Matthew Nichols, Pia A Elustondo, Jordan Warford, Aruloli Thirumaran, Evgeny V Pavlov, George S Robertson
The effects of global mitochondrial calcium (Ca(2+)) uniporter (MCU) deficiency on hypoxic-ischemic (HI) brain injury, neuronal Ca(2+) handling, bioenergetics and hypoxic preconditioning (HPC) were examined. Forebrain mitochondria isolated from global MCU nulls displayed markedly reduced Ca(2+) uptake and Ca(2+)-induced opening of the membrane permeability transition pore. Despite evidence that these effects should be neuroprotective, global MCU nulls and wild-type (WT) mice suffered comparable HI brain damage...
December 1, 2016: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/27879386/mitochondrial-calcium-homeostasis-implications-for-neurovascular-and-neurometabolic-coupling
#5
REVIEW
Sridhar S Kannurpatti
Mitochondrial function is critical to maintain high rates of oxidative metabolism supporting energy demands of both spontaneous and evoked neuronal activity in the brain. Mitochondria not only regulate energy metabolism, but also influence neuronal signaling. Regulation of "energy metabolism" and "neuronal signaling" (i.e. neurometabolic coupling), which are coupled rather than independent can be understood through mitochondria's integrative functions of calcium ion (Ca(2+)) uptake and cycling. While mitochondrial Ca(2+) do not affect hemodynamics directly, neuronal activity changes are mechanistically linked to functional hyperemic responses (i...
November 22, 2016: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/27859782/inhibition-of-the-mitochondrial-calcium-uniporter-mcu-rescues-dopaminergic-neurons-in-pink1-zebrafish
#6
Smijin Soman, Marcus Keatinge, Mahsa Moein, Marc DaCosta, Heather Mortiboys, Alexander Skupin, Sreedevi Sugunan, Michal Bazala, Jacek Kuznicki, Oliver Bandmann
Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of early onset Parkinson's disease (PD). Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter (MCU), located in the inner mitochondrial membrane, prevents dopaminergic neuronal cell loss in pink1(Y431) * mutant zebrafish (Danio rerio) via rescue of mitochondrial respiratory chain function...
November 12, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27827394/mitochondrial-ca-2-uptake-controls-actin-cytoskeleton-dynamics-during-cell-migration
#7
Julien Prudent, Nikolay Popgeorgiev, Rudy Gadet, Mathieu Deygas, Ruth Rimokh, Germain Gillet
Intracellular Ca(2+) signaling regulates cell migration by acting on cytoskeleton architecture, cell directionality and focal adhesions dynamics. In migrating cells, cytosolic Ca(2+) pool and Ca(2+) pulses are described as key components of these effects. Whereas the role of the mitochondrial calcium homeostasis and the Mitochondria Cacium Uniporter (MCU) in cell migration were recently highlighted in vivo using the zebrafish model, their implication in actin cystokeleton dynamics and cell migration in mammals is not totally characterized...
November 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27793988/crispr-cas9-mediated-endogenous-c-terminal-tagging-of-trypanosoma-cruzi-genes-reveals-the-acidocalcisome-localization-of-the-inositol-1-4-5-trisphosphate-receptor
#8
Noelia Lander, Miguel A Chiurillo, Melissa Storey, Anibal E Vercesi, Roberto Docampo
Methods for genetic manipulation of Trypanosoma cruzi, the etiologic agent of Chagas disease, have been highly inefficient, and no endogenous tagging of genes has been reported to date. We report here the use of the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated gene 9) system for endogenously tagging genes in this parasite. The utility of the method was established by tagging genes encoding proteins of known localization such as TcFCaBP (flagellar calcium binding protein) and TcVP1 (vacuolar proton pyrophosphatase), and two proteins of undefined or disputed localization, the TcMCU (mitochondrial calcium uniporter) and TcIP3R (inositol 1,4,5-trisphosphate receptor)...
December 2, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27692849/calcium-at-the-center-of-cell-signaling-interplay-between-endoplasmic-reticulum-mitochondria-and-lysosomes
#9
REVIEW
Anna Raffaello, Cristina Mammucari, Gaia Gherardi, Rosario Rizzuto
In recent years, rapid discoveries have been made relating to Ca(2+) handling at specific organelles that have important implications for whole-cell Ca(2+) homeostasis. In particular, the structures of the endoplasmic reticulum (ER) Ca(2+) 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 Ca(2+) signaling are milestones on the route towards a deeper comprehension of the complexity of global Ca(2+) signaling...
December 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27681178/expression-of-the-mitochondrial-calcium-uniporter-in-cardiac-myocytes-improves-impaired-mitochondrial-calcium-handling-and-metabolism-in-simulated-hyperglycemia
#10
Julieta Diaz-Juarez, Jorge Suarez, Federico Cividini, Brian T Scott, Tanja Diemer, Anzhi Dai, Wolfgang H Dillmann
Diabetic cardiomyopathy is associated with metabolic changes including decreased glucose oxidation (Gox) and increased fatty acid oxidation (FAox), which result in cardiac energetic deficiency. Diabetic hyperglycemia is a pathophysiological mechanism that triggers multiple maladaptive phenomena. The mitochondrial calcium uniporter (MCU) is the channel responsible for Ca(2+) uptake in mitochondria and free mitochondrial calcium concentration ([Ca(2+)]m) regulates mitochondrial metabolism. Experiments with cardiac myocytes (CM) exposed to simulated hyperglycemia revealed both reduced [Ca(2+)]m and MCU protein levels...
September 28, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27665468/mitochondrial-ca-2-uptake-pathways
#11
Pia A Elustondo, Matthew Nichols, George S Robertson, Evgeny V Pavlov
Calcium (Ca(2+)) plays diverse roles in all living organisms ranging from bacteria to humans. It is a structural element for bones, an essential mediator of excitation-contraction coupling, and a universal second messenger in the regulation of ion channel, enzyme and gene expression activities. In mitochondria, Ca(2+) is crucial for the control of energy production and cellular responses to metabolic stress. Ca(2+) uptake by the mitochondria occurs by the uniporter mechanism. The Mitochondrial Ca2+ Uniporter (MCU) protein has recently been identified as a core component responsible for mitochondrial Ca(2+) uptake...
September 24, 2016: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/27648837/mir-138-and-mir-25-downregulate-mcu-causing-pulmonary-arterial-hypertension-s-cancer-phenotype
#12
Zhigang Hong, Kuang-Hueih Chen, Asish Dasgupta, Francois Potus, Kimberly Dunham-Snary, Sebastien Bonnet, Lian Tian, Jennifer Fu, Sandra Breuils-Bonnet, Steeve Provencher, Danchen Wu, Jeffrey Mewburn, Mark L Ormiston, Stephen L Archer
RATIONALE: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cells (PASMC) proliferation, migration, and apoptosis-resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis and mitochondrial fission. OBJECTIVES: To determine how changes in mitochondrial calcium uniporter complex (MCUC) function influence mitochondrial dynamics and contribute to PAH's cancer-like phenotype...
September 20, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/27647893/critical-reappraisal-confirms-that-mitofusin-2-is-an-endoplasmic-reticulum-mitochondria-tether
#13
Deborah Naon, Marta Zaninello, Marta Giacomello, Tatiana Varanita, Francesca Grespi, Sowmya Lakshminaranayan, Annalisa Serafini, Martina Semenzato, Stephanie Herkenne, Maria Isabel Hernández-Alvarez, Antonio Zorzano, Diego De Stefani, Gerald W Dorn, Luca Scorrano
The discovery of the multiple roles of mitochondria-endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER-mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2's role in ER-mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER-mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27637331/strategic-positioning-and-biased-activity-of-the-mitochondrial-calcium-uniporter-in-cardiac-muscle
#14
Sergio De La Fuente, Celia Fernandez-Sanz, Caitlin Vail, Elorm J Agra, Kira Holmstrom, Junhui Sun, Jyotsna Mishra, Dewight Williams, Toren Finkel, Elizabeth Murphy, Suresh K Joseph, Shey-Shing Sheu, György Csordás
Control of myocardial energetics by Ca(2+) signal propagation to the mitochondrial matrix includes local Ca(2+) delivery from sarcoplasmic reticulum (SR) ryanodine receptors (RyR2) to the inner mitochondrial membrane (IMM) Ca(2+) uniporter (mtCU). mtCU activity in cardiac mitochondria is relatively low, whereas the IMM surface is large, due to extensive cristae folding. Hence, stochastically distributed mtCU may not suffice to support local Ca(2+) transfer. We hypothesized that mtCU concentrated at mitochondria-SR associations would promote the effective Ca(2+) transfer...
October 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27627464/privileged-crosstalk-between-trpv1-channels-and-mitochondrial-calcium-shuttling-machinery-controls-nociception
#15
Iulia I Nita, Yaki Caspi, Sagi Gudes, Dimitri Fishman, Shaya Lev, Michal Hersfinkel, Israel Sekler, Alexander M Binshtok
The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca(2+) uniporter - MCU, controls mitochondrial Ca(2+) entry while a sodium/calcium transporter - NCLX shapes calcium and sodium transients by mediating sodium entry into and removing calcium from the mitochondria...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27582500/the-effect-of-chronic-alcohol-consumption-on-mitochondrial-calcium-handling-in-hepatocytes
#16
Guoqiang Wang, Elisabeth Mémin, Ishwarya Murali, Lawrence D Gaspers
The damage to liver mitochondria is universally observed in both humans and animal models after excessive alcohol consumption.  Acute alcohol treatment has been shown to stimulate calcium (Ca(2+)) release from internal stores in hepatocytes.  The resultant increase in cytosolic Ca(2+) is expected to be accumulated by neighboring mitochondria, which could potentially lead to mitochondrial Ca(2+) overload and injury.  Our data indicate that total and free mitochondrial matrix Ca(2+) levels are, indeed, elevated in hepatocytes isolated from alcohol-fed rats compared to their pair-fed control littermates...
August 31, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27569754/structural-insights-into-mitochondrial-calcium-uniporter-regulation-by-divalent-cations
#17
Samuel K Lee, Santhanam Shanmughapriya, Mac C Y Mok, Zhiwei Dong, Dhanendra Tomar, Edmund Carvalho, Sudarsan Rajan, Murray S Junop, Muniswamy Madesh, Peter B Stathopulos
Calcium (Ca(2+)) flux into the matrix is tightly controlled by the mitochondrial Ca(2+) uniporter (MCU) due to vital roles in cell death and bioenergetics. However, the precise atomic mechanisms of MCU regulation remain unclear. Here, we solved the crystal structure of the N-terminal matrix domain of human MCU, revealing a β-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of Ca(2+) or Mg(2+) destabilizes and shifts the self-association equilibrium of the domain toward monomer...
September 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27568554/inhibiting-the-mitochondrial-calcium-uniporter-during-development-impairs-memory-in-adult-drosophila
#18
Ilaria Drago, Ronald L Davis
The uptake of cytoplasmic calcium into mitochondria is critical for a variety of physiological processes, including calcium buffering, metabolism, and cell survival. Here, we demonstrate that inhibiting the mitochondrial calcium uniporter in the Drosophila mushroom body neurons (MBn)-a brain region critical for olfactory memory formation-causes memory impairment without altering the capacity to learn. Inhibiting uniporter activity only during pupation impaired adult memory, whereas the same inhibition during adulthood was without effect...
September 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27500493/mitochondrial-calcium-uptake-underlies-ros-generation-during-aminoglycoside-induced-hair-cell-death
#19
Robert Esterberg, Tor Linbo, Sarah B Pickett, Patricia Wu, Henry C Ou, Edwin W Rubel, David W Raible
Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides...
September 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27477272/micu1-serves-as-a-molecular-gatekeeper-to-prevent-in%C3%A2-vivo-mitochondrial-calcium-overload
#20
Julia C Liu, Jie Liu, Kira M Holmström, Sara Menazza, Randi J Parks, Maria M Fergusson, Zu-Xi Yu, Danielle A Springer, Charles Halsey, Chengyu Liu, Elizabeth Murphy, Toren Finkel
MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1(-/-) mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1(-/-) mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP...
August 9, 2016: Cell Reports
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