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Mitochondrial pyruvate carrier

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https://www.readbyqxmd.com/read/29700317/pgc1%C3%AE-promotes-cholangiocarcinoma-metastasis-by-upregulating-pdha1-and-mpc1-expression-to-reverse-the-warburg-effect
#1
Dan Li, Chaoqun Wang, Panfei Ma, Qingan Yu, Mingqi Gu, Liqian Dong, Wenjing Jiang, Shangha Pan, Changming Xie, Jihua Han, Yaliang Lan, Jing Sun, Ping Sheng, Kunpeng Liu, Yaohua Wu, Lianxin Liu, Yong Ma, Hongchi Jiang
PGC1α acts as a central regulator of mitochondrial metabolism, whose role in cancer progression has been highlighted but remains largely undefined. Especially, it is completely unknown about the effect of PGC1α on cholangiocarcinoma (CCA). Here we showed that PGC1α overexpression had no impact on CCA growth despite the decreased expression of PGC1α in CCA compared with adjacent normal tissue. Instead, PGC1α overexpression-promoted CCA metastasis both in vitro and in vivo. Mechanistically, for the first time, we illuminated that PGC1α reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation...
April 27, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29669911/mpc1-is-essential-for-pgc-1%C3%AE-induced-mitochondrial-respiration-and-biogenesis
#2
Eunjin Koh, Young Kyung Kim, Daye Shin, Kyung-Sup Kim
Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is downregulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha (PGC-1α)...
April 18, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29572438/interruption-of-lactate-uptake-by-inhibiting-mitochondrial-pyruvate-transport-unravels-direct-antitumor-and-radiosensitizing-effects
#3
Cyril Corbet, Estelle Bastien, Nihed Draoui, Bastien Doix, Lionel Mignion, Bénédicte F Jordan, Arnaud Marchand, Jean-Christophe Vanherck, Patrick Chaltin, Olivier Schakman, Holger M Becker, Olivier Riant, Olivier Feron
Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro13 C-glucose and in vivo hyperpolarized13 C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation...
March 23, 2018: Nature Communications
https://www.readbyqxmd.com/read/29547090/prognostic-role-of-mitochondrial-pyruvate-carrier-in-isocitrate-dehydrogenase-mutant-glioma
#4
Michael Karsy, Jian Guan, L Eric Huang
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis...
March 16, 2018: Journal of Neurosurgery
https://www.readbyqxmd.com/read/29472561/human-mitochondrial-pyruvate-carrier-2-as-an-autonomous-membrane-transporter
#5
Raghavendra Sashi Krishna Nagampalli, José Edwin Neciosup Quesñay, Douglas Adamoski, Zeyaul Islam, James Birch, Heitor Gobbi Sebinelli, Richard Marcel Bruno Moreira Girard, Carolline Fernanda Rodrigues Ascenção, Angela Maria Fala, Bianca Alves Pauletti, Sílvio Roberto Consonni, Juliana Ferreira de Oliveira, Amanda Cristina Teixeira Silva, Kleber Gomes Franchini, Adriana Franco Paes Leme, Ariel Mariano Silber, Pietro Ciancaglini, Isabel Moraes, Sandra Martha Gomes Dias, Andre Luis Berteli Ambrosio
The active transport of glycolytic pyruvate across the inner mitochondrial membrane is thought to involve two mitochondrial pyruvate carrier subunits, MPC1 and MPC2, assembled as a 150 kDa heterotypic oligomer. Here, the recombinant production of human MPC through a co-expression strategy is first described; however, substantial complex formation was not observed, and predominantly individual subunits were purified. In contrast to MPC1, which co-purifies with a host chaperone, we demonstrated that MPC2 homo-oligomers promote efficient pyruvate transport into proteoliposomes...
February 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29444156/protein-s-glutathionylation-lowers-superoxide-hydrogen-peroxide-release-from-skeletal-muscle-mitochondria-through-modification-of-complex-i-and-inhibition-of-pyruvate-uptake
#6
Robert M Gill, Marisa O'Brien, Adrian Young, Danielle Gardiner, Ryan J Mailloux
Protein S-glutathionylation is a reversible redox modification that regulates mitochondrial metabolism and reactive oxygen species (ROS) production in liver and cardiac tissue. However, whether or not it controls ROS release from skeletal muscle mitochondria has not been explored. In the present study, we examined if chemically-induced protein S-glutathionylation could alter superoxide (O2●-)/hydrogen peroxide (H2O2) release from isolated muscle mitochondria. Disulfiram, a powerful chemical S-glutathionylation catalyst, was used to S-glutathionylate mitochondrial proteins and ascertain if it can alter ROS production...
2018: PloS One
https://www.readbyqxmd.com/read/29336483/glucose-metabolism-during-in-vitro-maturation-of-mouse-oocytes-an-study-using-rna-interference
#7
Hong-Li Xie, Shuai Zhu, Jie Zhang, Jing Wen, Hong-Jie Yuan, Liu-Zhu Pan, Ming-Jiu Luo, Jing-He Tan
In previous studies on glucose metabolism during in vitro maturation, intact cumulus-oocyte complexes (COCs) were treated with enzyme inhibitors/activators. Because inhibitors/activators may have non-specificity and/or toxicity, and culture of COCs cannot differentiate whether glucose metabolism of cumulus cells (CCs) or that of the oocyte supports oocyte maturation, results from the previous studies must be verified by silencing genes in either CCs or cumulus-denuded oocytes (DOs). In this study, RNAi was adopted to specify the effects of glucose metabolism in CCs or DOs on oocyte maturation...
January 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29286150/mitochondrial-pyruvate-carrier-modulates-the-epithelial-mesenchymal-transition-in-cholangiocarcinoma
#8
Tomofumi Ohashi, Hidetoshi Eguchi, Koichi Kawamoto, Masamitsu Konno, Ayumu Asai, Hugh Colvin, Yuji Ueda, Hirofumi Takaoka, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Shogo Kobayashi, Jun Koseki, Taroh Satoh, Kazuhiko Ogawa, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Intrahepatic cholangiocarcinoma (ICC) is known to have a high malignant potential. Because of its high recurrence rate, ICC has a poor prognosis even after complete tumor resection. Compared with normal differentiated cells, cancer cells have an altered metabolism for supporting their survival in severe conditions. Cancer cells acquire additional malignant potential as a result of this metabolic alteration. Thus, the molecules known to be involved in cancer metabolism, could be novel therapeutic targets. The mitochondrial pyruvate carrier (MPC) is a recently discovered pyruvate transporter, which is located in the mitochondrial inner membrane...
March 2018: Oncology Reports
https://www.readbyqxmd.com/read/29243009/adrenaline-induces-mitochondrial-biogenesis-in-rat-liver
#9
Gaetana Napolitano, Daniela Barone, Sergio Di Meo, Paola Venditti
We studied the effects of adrenaline administration and depletion (induced by reserpine) on rat liver oxidative metabolism. We showed that adrenaline increases, and reserpine decreases aerobic capacity (inferred by cytochrome oxidase activity) in tissue modifying the hepatic content of mitochondrial proteins without changing mitochondrial aerobic capacity. The changes in tissue cytochrome oxidase activity, which agreed with the expression levels of factors involved in mitochondrial biogenesis, such as PGC-1, NRF-1, and NRF-2, were associated with similar changes in tissue and mitochondrial State 3 respiration...
February 2018: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/29175325/fatty-acid-oxidation-alleviates-the-energy-deficiency-caused-by-the-loss-of-mpc1-in-mpc1-mice
#10
Shiying Zou, Tianqi Lang, Boyang Zhang, Kunlun Huang, Lijing Gong, Haosu Luo, Wentao Xu, Xiaoyun He
Pyruvate is a central substrate in energy metabolism, paramount to carbohydrate, fat, and amino acid catabolic and anabolic pathways. Mitochondrial pyruvate carrier 1(MPC1) is one important component of the complex that facilitates mitochondrial pyruvate import. Complete MPC1 deficiency is a serious concern, and has been shown to result in embryonic lethality in mice. The study outlined in this paper generated one mouse line with the MPC1 protein part deficiency by using the CRISPR/Cas9 system. Clinical observations, body weight and organ/tissue weight, gas exchange, cold-stimulation, blood parameters, as well as histopathology analysis were analyzed to evaluate potential physiological abnormalities caused by MPC1 deficiency...
January 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29166881/mitochondrial-pyruvate-carrier-1-mediates-abscisic-acid-regulated-stomatal-closure-and-the-drought-response-by-affecting-cellular-pyruvate-content-in-arabidopsis-thaliana
#11
Jian-Lin Shen, Chun-Long Li, Mei Wang, Li-Long He, Min-Yan Lin, Dong-Hua Chen, Wei Zhang
BACKGROUND: Stomata are micropores surrounded by pairs of guard cells, and their opening is finely controlled to balance water vapor loss as transpiration and CO2 absorption for photosynthesis. The regulatory signaling network for stomatal movement is complicated, and increasing numbers of new genes have been shown to be involved in this process. Our previous study indicated that a member of the plant putative mitochondrial pyruvate carrier (MPC) family, NRGA1, is a negative regulator of guard cell abscisic acid (ABA) signaling...
November 22, 2017: BMC Plant Biology
https://www.readbyqxmd.com/read/29156584/identification-of-physiological-substrates-and-binding-partners-of-the-plant-mitochondrial-protease-ftsh4-by-the-trapping-approach
#12
Magdalena Opalińska, Katarzyna Parys, Hanna Jańska
Maintenance of functional mitochondria is vital for optimal cell performance and survival. This is accomplished by distinct mechanisms, of which preservation of mitochondrial protein homeostasis fulfills a pivotal role. In plants, inner membrane-embedded i -AAA protease, FTSH4, contributes to the mitochondrial proteome surveillance. Owing to the limited knowledge of FTSH4's in vivo substrates, very little is known about the pathways and mechanisms directly controlled by this protease. Here, we applied substrate trapping coupled with mass spectrometry-based peptide identification in order to extend the list of FTSH4's physiological substrates and interaction partners...
November 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29126303/inhibition-of-the-mitochondrial-pyruvate-carrier-by-tolylfluanid
#13
Yana Chen, Kyle S McCommis, Daniel Ferguson, Angela M Hall, Charles A Harris, Brian N Finck
Several recent studies have suggested that compounds known as endocrine-disrupting chemicals (EDCs) can promote obesity by serving as ligands for nuclear receptors, including the peroxisome proliferator-activated receptor γ (PPARγ) and the glucocorticoid receptor (GR). Thiazolidinedione insulin sensitizers, which act as ligands for PPARγ, also interact with and regulate the activity of the mitochondrial pyruvate carrier (MPC). We evaluated whether several EDCs might also affect MPC activity. Most of the EDCs evaluated did not acutely affect pyruvate metabolism...
February 1, 2018: Endocrinology
https://www.readbyqxmd.com/read/29107293/the-mitochondrial-pyruvate-carrier-mediates-high-fat-diet-induced-increases-in-hepatic-tca-cycle-capacity
#14
Adam J Rauckhorst, Lawrence R Gray, Ryan D Sheldon, Xiaorong Fu, Alvin D Pewa, Charlotte R Feddersen, Adam J Dupuy, Katherine N Gibson-Corley, James E Cox, Shawn C Burgess, Eric B Taylor
OBJECTIVE: Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions...
November 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29044478/enhanced-pyruvate-production-in-candida-glabrata-by-carrier-engineering
#15
Zhengshan Luo, Song Liu, Guocheng Du, Sha Xu, Jingwen Zhou, Jian Chen
Pyruvate is an important organic acid that plays a key role in the central metabolic pathway. Manipulating transporters is an efficient strategy to enhance production of target organic acids and a means to understand the effects of altered intracellular pyruvate content on global metabolic networks. Efforts have been made to manipulate mitochondrial pyruvate carrier (MPC) to transport pyruvate into different subcellular compartments in Candida glabrata to demonstrate the effects of the subcellular distribution of pyruvate on central carbon metabolism...
February 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28923861/mct1-inhibitor-azd3965-increases-mitochondrial-metabolism-facilitating-combination-therapy-and-noninvasive-magnetic-resonance-spectroscopy
#16
Mounia Beloueche-Babari, Slawomir Wantuch, Teresa Casals Galobart, Markella Koniordou, Harold G Parkes, Vaitha Arunan, Yuen-Li Chung, Thomas R Eykyn, Paul D Smith, Martin O Leach
Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux...
November 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28867301/nonalcoholic-fatty-liver-disease-as-a-nexus-of-metabolic-and-hepatic-diseases
#17
REVIEW
Varman T Samuel, Gerald I Shulman
NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available...
January 9, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/28812582/control-of-intestinal-stem-cell-function-and-proliferation-by-mitochondrial-pyruvate-metabolism
#18
John C Schell, Dona R Wisidagama, Claire Bensard, Helong Zhao, Peng Wei, Jason Tanner, Aimee Flores, Jeffrey Mohlman, Lise K Sorensen, Christian S Earl, Kristofor A Olson, Ren Miao, T Cameron Waller, Don Delker, Priyanka Kanth, Lei Jiang, Ralph J DeBerardinis, Mary P Bronner, Dean Y Li, James E Cox, Heather R Christofk, William E Lowry, Carl S Thummel, Jared Rutter
Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28812580/lactate-dehydrogenase-activity-drives-hair-follicle-stem-cell-activation
#19
Aimee Flores, John Schell, Abigail S Krall, David Jelinek, Matilde Miranda, Melina Grigorian, Daniel Braas, Andrew C White, Jessica L Zhou, Nicholas A Graham, Thomas Graeber, Pankaj Seth, Denis Evseenko, Hilary A Coller, Jared Rutter, Heather R Christofk, William E Lowry
Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28624784/mitochondrial-pyruvate-carrier-function-determines-cell-stemness-and-metabolic-reprogramming-in-cancer-cells
#20
Xiaoli Li, Gaoyang Han, Xiaoran Li, Quancheng Kan, Zhirui Fan, Yaqing Li, Yasai Ji, Jing Zhao, Mingzhi Zhang, Mantas Grigalavicius, Viktor Berge, Mariusz Adam Goscinski, Jahn M Nesland, Zhenhe Suo
One of the remarkable features of cancer cells is aerobic glycolysis, a phenomenon known as the "Warburg Effect", in which cells rely preferentially on glycolysis instead of oxidative phosphorylation (OXPHOS) as the main energy source even in the presence of high oxygen tension. Cells with dysfunctional mitochondria are unable to generate sufficient ATP from mitochondrial OXPHOS, and then are forced to rely on glycolysis for ATP generation. Here we report our results in a prostate cancer cell line in which the mitochondrial pyruvate carrier 1 (MPC1) gene was knockout...
July 11, 2017: Oncotarget
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