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Mitochondrial calcium uniporter

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...
September 28, 2016: Trends in Biochemical Sciences
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
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
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
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
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 Ca2+ signal propagation to the mitochondrial matrix includes local Ca2+ delivery from sarcoplasmic reticulum (SR) ryanodine receptors (RyR2) to the inner mitochondrial membrane (IMM) Ca2+ uniporter (mtCU). mtCU activity in cardiac mitochondria is relatively low, while the IMM surface is large, due to extensive cristae folding. Hence, stochastically distributed mtCU may not suffice to support local Ca2+ transfer. We hypothesized that mtCU concentrated at mitochondria-SR associations would promote the effective Ca2+ transfer...
September 16, 2016: Journal of Biological Chemistry
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...
September 11, 2016: Biochimica et Biophysica Acta
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
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
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
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
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
Erik Bonke, Ilka Siebels, Klaus Zwicker, Stefan Dröse
Manganese-induced toxicity has been linked to mitochondrial dysfunction and an increased generation of reactive oxygen species (ROS). We could recently show in mechanistic studies that Mn(2+) ions induce hydrogen peroxide (H2O2) production from the ubiquinone binding site of mitochondrial complex II (IIQ) and generally enhance H2O2 formation by accelerating the rate of superoxide dismutation. The present study with intact mitochondria reveals that manganese additionally enhances H2O2 emission by inducing mitochondrial permeability transition (mPT)...
July 26, 2016: Free Radical Biology & Medicine
Xi Chen, Yu Zhang, Bin Xu, Zhongqi Cai, Lin Wang, Jinwen Tian, Yuqi Liu, Yang Li
Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA(Ile) A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca(2+) cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA(Ile) A4263G mutation. The mitochondrial calcium ([Ca(2+)]m) in cells from hypertensive subjects with the tRNA(Ile) A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P<0...
September 2016: International Journal of Biochemistry & Cell Biology
Xiaohui Zhang, Xiaohua Zhang, Yiqun Xiong, Chaoying Xu, Xinliang Liu, Jian Lin, Guiping Mu, Shaogang Xu, Wenhe Liu
The sarcolemmal ATP-sensitive K+ (sarcKATP) channel plays a cardioprotective role during stress. However, the role of the sarcKATP channel in the apoptosis of cardiomyocytes and association with mitochondrial calcium remains unclear. For this purpose, we developed a model of LPS-induced sepsis in neonatal rat cardiomyocytes (NRCs). The TUNEL assay was performed in order to detect the apoptosis of cardiac myocytes and the MTT assay was performed to determine cellular viability. Exposure to LPS significantly decreased the viability of the NRCs as well as the expression of Bcl-2, whereas it enhanced the activity and expression of the apoptosis-related proteins caspase-3 and Bax, respectively...
September 2016: International Journal of Molecular Medicine
Seok-Kyu Kwon, Richard Sando, Tommy L Lewis, Yusuke Hirabayashi, Anton Maximov, Franck Polleux
Individual synapses vary significantly in their neurotransmitter release properties, which underlie complex information processing in neural circuits. Presynaptic Ca2+ homeostasis plays a critical role in specifying neurotransmitter release properties, but the mechanisms regulating synapse-specific Ca2+ homeostasis in the mammalian brain are still poorly understood. Using electrophysiology and genetically encoded Ca2+ sensors targeted to the mitochondrial matrix or to presynaptic boutons of cortical pyramidal neurons, we demonstrate that the presence or absence of mitochondria at presynaptic boutons dictates neurotransmitter release properties through Mitochondrial Calcium Uniporter (MCU)-dependent Ca2+ clearance...
July 2016: PLoS Biology
I B Zavodnik
Са2+ is a very important and versatile intracellular signal which controls numerous biochemical and physiological (pathophysiological) processes in the cell. Good evidence exists that mitochondria are sensors, decoders and regulators of calcium signaling. Precise regulation of calcium signaling in the cell involves numerous molecular targets, which induce and decode changes of Са2+ concentrations in the cell (pumps, channels, Са2+-binding proteins, Са2+-dependent enzymes, localized in the cytoplasm and organelles)...
March 2016: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
Jinxing Song, Xiao Liu, Pengfei Zhai, Jingjing Huang, Ling Lu
Ca(2+) uptake into mitochondria plays a central role in cell physiology by stimulating ATP production, shaping cytosolic Ca(2+) transients and regulating cell survival or death. Although this system has been studied extensively in mammalian cells, the physiological implications of Ca(2+) uptake into mitochondria in fungal cells are still unknown. In this study, a bi-directional best-hit BLASTP search revealed that the genome of Aspergillus fumigatus encodes a homolog of a putative mitochondrial Ca(2+) uniporter (MCU) and a mitochondrial carrier protein AGC1/MICU1 homolog...
September 2016: Fungal Genetics and Biology: FG & B
Olga Akopova, Anatoly Kotsiuruba, Yulia Korkach, Liudmila Kolchinskaya, Valentina Nosar, Bronislav Gavenauskas, Zoya Serebrovska, Iryna Mankovska, Vadim Sagach
BACKGROUND/AIMS: NO and reactive nitrogen species (RNS) are thought to be physiologically important effectors of mitochondrial calcium transport, but this issue was not studied in a living organism. According to literature, the modulation of Ca2+ uptake could influence RNS production via the action on mitochondrial NO synthase (mtNOS). The aim of this work was to study the effect of in vivo administration of NO donor nitroglycerine (NG) on matrix Ca2+ accumulation, RNS production and mtNOS activity...
2016: Cellular Physiology and Biochemistry
Zhaolong Xu, Dayong Zhang, Xiaolan He, Yihong Huang, Hongbo Shao
To uptake calcium ions of mitochondria is of significant functional connotation for cells, because calcium ions in mitochondria are involved in energy production, regulatory signals transfer, and mitochondrial permeability transition pore opening and even programmed cell death of apoptosis, further playing more roles in plant productivity and quality. Cytoplasmic calcium ions access into outer mitochondrial membrane (OMM) from voltage dependent anion-selective channel (VDAC) and were absorbed into inner mitochondrial membrane (IMM) by mitochondrial calcium uniporter (MCU), rapid mitochondrial calcium uptake (RaM) or mitochondrial ryanodine receptor (mRyR)...
June 2016: Current Genomics
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