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Mitochondrial calcium uniporter

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https://www.readbyqxmd.com/read/29142021/inf2-mediated-actin-polymerization-at-the-er-stimulates-mitochondrial-calcium-uptake-inner-membrane-constriction-and-division
#1
Rajarshi Chakrabarti, Wei-Ke Ji, Radu V Stan, Jaime de Juan Sanz, Timothy A Ryan, Henry N Higgs
Mitochondrial division requires division of both the inner and outer mitochondrial membranes (IMM and OMM, respectively). Interaction with endoplasmic reticulum (ER) promotes OMM division by recruitment of the dynamin Drp1, but effects on IMM division are not well characterized. We previously showed that actin polymerization through ER-bound inverted formin 2 (INF2) stimulates Drp1 recruitment in mammalian cells. Here, we show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: a rise in mitochondrial matrix calcium through the mitochondrial calcium uniporter...
November 15, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29137386/mitochondrial-calcium-uniporter-as-a-target-of-microrna-340-and-promoter-of-metastasis-via-enhancing-the-warburg-effect
#2
Changhui Yu, Yuhao Wang, Jiawen Peng, Qiang Shen, Mimi Chen, Wei Tang, Xiumei Li, Chunqing Cai, Bin Wang, Shaoxi Cai, Xiaojing Meng, Fei Zou
Background: A shift from oxygen phosphorylation to aerobic glycolysis was known as the Warburg effect and a characteristic of cancer cell metabolism facilitating metastasis. Mitochondrial calcium uniporter (MCU), a key ion channel that mediates Ca(2+) uptake into mitochondria, was found to promote cancer progression and metastasis. However, its explicit role in shifting metabolism of breast cancer cells has not been defined. Methods: We evaluated MCU overexpression or knock-down on migration, invasion and glucose metabolismin breast cancer cells...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29073106/cardiovascular-homeostasis-dependence-on-micu2-a-regulatory-subunit-of-the-mitochondrial-calcium-uniporter
#3
Alexander G Bick, Hiroko Wakimoto, Kimberli J Kamer, Yasemin Sancak, Olga Goldberger, Anna Axelsson, Daniel M DeLaughter, Joshua M Gorham, Vamsi K Mootha, J G Seidman, Christine E Seidman
Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2(-/-) mice. Mutant mice had left atrial enlargement and Micu2(-/-) cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2(-/-) ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (Micu2(-/-) vs...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29073097/content-of-mitochondrial-calcium-uniporter-mcu-in-cardiomyocytes-is-regulated-by-microrna-1-in-physiologic-and-pathologic-hypertrophy
#4
Tania Zaglia, Paola Ceriotti, Antonio Campo, Giulia Borile, Andrea Armani, Pierluigi Carullo, Valentina Prando, Raffaele Coppini, Vladimiro Vida, Tomas O Stølen, Wisløff Ulrik, Elisabetta Cerbai, Giovanni Stellin, Giuseppe Faggian, Diego De Stefani, Marco Sandri, Rosario Rizzuto, Fabio Di Lisa, Tullio Pozzan, Daniele Catalucci, Marco Mongillo
The mitochondrial Ca(2+) uniporter complex (MCUC) is a multimeric ion channel which, by tuning Ca(2+) influx into the mitochondrial matrix, finely regulates metabolic energy production. In the heart, this dynamic control of mitochondrial Ca(2+) uptake is fundamental for cardiomyocytes to adapt to either physiologic or pathologic stresses. Mitochondrial calcium uniporter (MCU), which is the core channel subunit of MCUC, has been shown to play a critical role in the response to β-adrenoreceptor stimulation occurring during acute exercise...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29053821/a-null-mutation-in-micu2-causes-abnormal-mitochondrial-calcium-homeostasis-and-a-severe-neurodevelopmental-disorder
#5
Hanan E Shamseldin, Ali Alasmari, Mohammed A Salih, Manar M Samman, Shahid A Mian, Tarfa Alshidi, Niema Ibrahim, Mais Hashem, Eissa Faqeih, Futwan Al-Mohanna, Fowzan S Alkuraya
Mitochondrial calcium homeostasis is a tightly controlled process that is required for a variety of cellular functions. The mitochondrial calcium uniporter complex plays a critical role in this process. MICU2 is a major component of the mitochondrial calcium uniporter complex and its deficiency has been shown to impair mitochondrial calcium [Ca2+]m homeostasis although the exact mechanism remains unclear. We used exome sequencing, positional mapping, and functional characterization of MICU2 deficiency to investigate the role of MICU2 in calcium homeostasis...
November 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29047093/cross-talk-between-mitochondrial-reactive-oxygen-species-and-sarcoplasmic-reticulum-calcium-in-pulmonary-arterial-smooth-muscle-cells
#6
Tengyao Song, Yun-Min Zheng, Yong-Xiao Wang
Hypoxic pulmonary vasoconstriction (HPV) occurs during both fetal and postnatal development and plays a critical role in matching regional alveolar perfusion with ventilation in humans and animals. HPV also contributes significantly to the development of pulmonary hypertension. Although the molecular mechanisms of HPV and pulmonary hypertension remain incompletely understood, increasing evidence demonstrates that hypoxia induces an elevated intracellular reactive oxygen species concentration ([ROS]i) in pulmonary artery smooth muscle cells (PASMCs)...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29038245/mitochondrial-calcium-dysregulation-contributes-to-dendrite-degeneration-mediated-by-pd-lbd-associated-lrrk2-mutants
#7
Manish Verma, Jason Callio, P Anthony Otero, Israel Sekler, Zachary P Wills, Charleen T Chu
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs prior to the well-characterized phenotype of dendritic shortening...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28990420/synaptic-activity-protects-neurons-against-calcium-mediated-oxidation-and-contraction-of-mitochondria-during-excitotoxicity
#8
Constanze Depp, Carlos Bas-Orth, Lisa Schroeder, Andrea Hellwig, Hilmar Bading
AIMS: Excitotoxicity triggered by extrasynaptic N-methyl-d-aspartate-type glutamate receptors has been implicated in many neurodegenerative conditions, including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Mitochondrial calcium overload leading to mitochondrial dysfunction represents an early event in excitotoxicity. Neurons are rendered resistant to excitotoxicity by previous periods of synaptic activity that activates a nuclear calcium-driven neuroprotective gene program...
November 14, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28962857/mitochondrial-cardiomyopathies-feature-increased-uptake-and-diminished-efflux-of-mitochondrial-calcium
#9
Salah Sommakia, Patrick R Houlihan, Sadiki S Deane, Judith A Simcox, Natalia S Torres, Mi-Young Jeong, Dennis R Winge, Claudio J Villanueva, Dipayan Chaudhuri
Calcium (Ca(2+)) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca(2+) transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca(2+) may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes...
December 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28947137/hint2-triggers-mitochondrial-ca-2-influx-by-regulating-the-mitochondrial-ca-2-uniporter-mcu-complex-and-enhances-gemcitabine-apoptotic-effect-in-pancreatic-cancer
#10
Linghui Chen, Qiang Sun, Dongkai Zhou, Wei Song, Qifan Yang, Bingjie Ju, Lufei Zhang, Haiyang Xie, Lin Zhou, Zhenhua Hu, Hangping Yao, Shusen Zheng, Weilin Wang
In early studies, it was shown that HINT2, which sensitizes cells to mitochondrial apoptosis, is down-regulated in hepatocellular carcinoma (HCC) cells (Martin et al., 2006). However, the molecular mechanism of this effect is unknown. Immunohistochemistry revealed that HINT2 expression is relatively low in pancreatic cancer tissues, compared to that in adjacent tissues (P < 0.05). Furthermore, its expression was related to pathological grade and lymph node metastasis (P = 0.0161 and 0.0108, respectively); in addition, down-regulation of HINT2 was found to be associated with relatively poor prognosis in pancreatic cancer patients...
September 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28944215/endoplasmic-reticulum-mitochondria-calcium-communication-and-the-regulation-of-mitochondrial-metabolism-in-cancer-a-novel-potential-target
#11
REVIEW
Galdo Bustos, Pablo Cruz, Alenka Lovy, César Cárdenas
Cancer is characterized by an uncontrolled cell proliferation rate even under low nutrient availability, which is sustained by a metabolic reprograming now recognized as a hallmark of cancer. Warburg was the first to establish the relationship between cancer and mitochondria; however, he interpreted enhanced aerobic glycolysis as mitochondrial dysfunction. Today it is accepted that many cancer cell types need fully functional mitochondria to maintain their homeostasis. Calcium (Ca(2+))-a key regulator of several cellular processes-has proven to be essential for mitochondrial metabolism...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28942921/mitochondrial-fission-promotes-the-continued-clearance-of-apoptotic-cells-by-macrophages
#12
Ying Wang, Manikandan Subramanian, Arif Yurdagul, Valéria C Barbosa-Lorenzi, Bishuang Cai, Jaime de Juan-Sanz, Timothy A Ryan, Masatoshi Nomura, Frederick R Maxfield, Ira Tabas
Clearance of apoptotic cells (ACs) by phagocytes (efferocytosis) prevents post-apoptotic necrosis and dampens inflammation. Defective efferocytosis drives important diseases, including atherosclerosis. For efficient efferocytosis, phagocytes must be able to internalize multiple ACs. We show here that uptake of multiple ACs by macrophages requires dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which is triggered by AC uptake. When mitochondrial fission is disabled, AC-induced increase in cytosolic calcium is blunted owing to mitochondrial calcium sequestration, and calcium-dependent phagosome formation around secondarily encountered ACs is impaired...
October 5, 2017: Cell
https://www.readbyqxmd.com/read/28939404/inhibition-of-the-mitochondrial-calcium-uniporter-inhibits-a%C3%AE-induced-apoptosis-by-reducing-reactive-oxygen-species-mediated-endoplasmic-reticulum-stress-in-cultured-microglia
#13
Nanchang Xie, Chuanjie Wu, Cui Wang, Xuan Cheng, Lu Zhang, Haifeng Zhang, Yajun Lian
Amyloid-beta (Aβ) has been shown to induce microglial apoptosis, which is itself sensitive to disturbed mitochondrial calcium (Ca(2+)) homeostasis. The mitochondrial calcium uniporter (MCU) plays an important regulatory role in mitochondrial Ca(2+) homeostasis, but its role in Aβ-induced microglia apoptosis is unknown. In this study, we found increased mitochondrial Ca(2+) concentration in Aβ-treated primary microglia and BV-2 cells; also, the MCU inhibitor Ru360 significantly attenuated Aβ-induced microglial apoptosis, whereas the MCU activator spermine augmented it...
December 1, 2017: Brain Research
https://www.readbyqxmd.com/read/28938844/mcur1-mediated-mitochondrial-calcium-signaling-facilitates-cell-survival-of-hepatocellular-carcinoma-via-reactive-oxygen-species-dependent-p53-degradation
#14
Tingting Ren, Jiaojiao Wang, Hui Zhang, Peng Yuan, Jianjun Zhu, Yousheng Wu, Qichao Huang, Xu Guo, Jing Zhang, Lele Ji, Jibin Li, Hongxin Zhang, Hushan Yang, Jinliang Xing
AIMS: Levels of the mitochondrial calcium uniporter regulator 1 (MCUR1) increases during development of hepatocellular carcinoma (HCC). However, mechanisms of how mitochondrial Ca(2+) homeostasis is modulated and its function remain limited in cancers. RESULTS: MCUR1 was frequently upregulated in HCC cells to enhance the Ca(2+) uptake into mitochondria in an MCU-dependent manner, which significantly facilitated cell survival by inhibiting mitochondria-dependent intrinsic apoptosis and promoting proliferation of HCC cells, and thus led to poor prognosis...
November 1, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28916471/the-pyk2-mcu-pathway-in-the-rat-middle-cerebral-artery-occlusion-model-of-ischemic-stroke
#15
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
#16
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
#17
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
#18
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...
September 1, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28838811/mitochondrial-calcium-imbalance-in-parkinson-s-disease
#19
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
#20
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
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