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Mitochondrial pyruvate carrier

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https://www.readbyqxmd.com/read/28154187/decreased-mitochondrial-pyruvate-transport-activity-in-the-diabetic-heart-role-of-mpc2-acetylation
#1
Shraddha S Vadvalkar, Satoshi Matsuzaki, Craig A Eyster, Jennifer R Giorgione, Lee B Bockus, Caroline S Kinter, Michael Kinter, Kenneth M Humphries
Alterations in mitochondrial function contribute to diabetic cardiomyopathy. We have previously shown that heart mitochondrial proteins are hyper-acetylated in OVE26 mice, a transgenic model of type 1 diabetes. However, the universality of this modification and its functional consequences are not well established. In this study, we demonstrate that Akita type 1 diabetic mice exhibit hyper-acetylation. Functionally, isolated Akita heart mitochondria have significantly impaired maximal (state 3) respiration with physiological pyruvate (0...
February 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28027586/targeting-the-mitochondrial-pyruvate-carrier-attenuates-fibrosis-in-a-mouse-model-of-nonalcoholic-steatohepatitis
#2
Kyle S McCommis, Wesley T Hodges, Elizabeth M Brunt, ILKe Nalbantoglu, William G McDonald, Christopher Holley, Hideji Fujiwara, Jean E Schaffer, Jerry R Colca, Brian N Finck
: Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease (NAFLD) is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin-sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose-limiting side effects thought to be due to activation of the peroxisome proliferator-activated receptor γ (PPARγ)...
December 27, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28012622/variable-liver-fat-concentration-as-a-proxy-for-body-fat-mobilization-postpartum-has-minor-effects-on-insulin-induced-changes-in-hepatic-gene-expression-related-to-energy-metabolism-in-dairy-cows
#3
C Weber, C T Schäff, U Kautzsch, S Börner, S Erdmann, R M Bruckmaier, M Röntgen, B Kuhla, H M Hammon
The liver plays a central role in adaptation for energy requirements around calving, and changes in the effects of insulin on hepatic energy metabolism contribute to metabolic adaptation in dairy cows. Hepatic insulin effects may depend on body fat mobilization. The objective of this study was to investigate the effects of insulin on the hepatic gene expression of enzymes involved in energy metabolism and factors related to nutrition partitioning in cows with high and low total liver fat concentration (LFC) after calving...
February 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28003588/effectiveness-of-medium-chain-triglyceride-oil-therapy-in-two-japanese-citrin-deficient-siblings-evaluation-using-oral-glucose-tolerance-tests
#4
Hiroki Otsuka, Hideo Sasai, Elsayed Abdelkreem, Norio Kawamoto, Minako Kawamoto, Toshiya Kamiya, Yasuo Tanimoto, Atsuo Kikuchi, Shigeo Kure, Chikahiko Numakura, Kiyoshi Hayasaka, Toshiyuki Fukao
Citrin deficiency, an inherited defect of the liver-type mitochondrial aspartate/glutamate carrier isoform (citrin), may cause impairment of glycolysis because of an increase in the cytosolic NADH/NAD(+) ratio. We report a Japanese boy whose main complaint was recurrent hypoglycemic episodes. He was suspected as having citrin deficiency because of his peculiar preference for protein- and fat-rich food. His young sister also had a similar food preference. Both siblings were diagnosed with citrin deficiency by genetic analysis...
2016: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27928028/mitochondrial-pyruvate-carrier-regulates-autophagy-inflammation-and-neurodegeneration-in-experimental-models-of-parkinson-s-disease
#5
Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N Hildebrandt, Jennifer A Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, William G McDonald, Martha L Escobar Galvis, Jeffrey H Kordower, Jeremy M Van Raamsdonk, Jerry R Colca, Patrik Brundin
Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP(+)) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein-based Caenorhabditis elegans model...
December 7, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27913098/succinyl-coa-synthetase-sucla2-deficiency-in-two-siblings-with-impaired-activity-of-other-mitochondrial-oxidative-enzymes-in-skeletal-muscle-without-mitochondrial-dna-depletion
#6
Xiaoping Huang, Jirair K Bedoyan, Didem Demirbas, David J Harris, Alexander Miron, Simone Edelheit, George Grahame, Suzanne D DeBrosse, Lee-Jun Wong, Charles L Hoppel, Douglas S Kerr, Irina Anselm, Gerard T Berry
Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype...
November 12, 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27911865/mitochondrial-pyruvate-carrier-function-is-negatively-linked-to-warburg-phenotype-in-vitro-and-malignant-features-in-esophageal-squamous-cell-carcinomas
#7
Yaqing Li, Xiaoran Li, Quancheng Kan, Mingzhi Zhang, Xiaoli Li, Ruiping Xu, Junsheng Wang, Dandan Yu, Mariusz Adam Goscinski, Jian-Guo Wen, Jahn M Nesland, Zhenhe Suo
Aerobic glycolysis is one of the emerging hallmarks of cancer cells. In this study, we investigated the relationship between blocking mitochondrial pyruvate carrier (MPC) with MPC blocker UK5099 and the metabolic alteration as well as aggressive features of esophageal squamous carcinoma. It was found that blocking pyruvate transportation into mitochondria attenuated mitochondrial oxidative phosphorylation (OXPHOS) and triggered aerobic glycolysis, a feature of Warburg effect. In addition, the HIF-1α expression and ROS production were also activated upon UK5099 application...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27872198/in-female-rat-heart-mitochondria-oophorectomy-results-in-loss-of-oxidative-phosphorylation
#8
Natalia Pavón, Alfredo Cabrera-Orefice, Juan Carlos Gallardo-Pérez, Cristina Uribe-Alvarez, Nadia A Rivero-Segura, Edgar Ricardo Vazquez-Martínez, Marco Cerbón, Eduardo Martínez-Abundis, Juan Carlos Torres-Narvaez, Raúl Martínez-Memije, Francisco-Javier Roldán-Gómez, Salvador Uribe-Carvajal
Oophorectomy in adult rats affected cardiac mitochondrial function. Progression of mitochondrial alterations was assessed at one, two and three months after surgery: at one month, very slight changes were observed, which increased at two and three months. Gradual effects included decrease in the rates of oxygen consumption and in respiratory uncoupling in the presence of complex I substrates, as well as compromised Ca(2+) buffering ability. Malondialdehyde concentration increased, whereas the ROS-detoxifying enzyme Mn(2+) superoxide dismutase (MnSOD) and aconitase lost activity...
February 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/27852261/mpc1-and-mpc2-expressions-are-associated-with-favorable-clinical-outcomes-in-prostate-cancer
#9
Xiaoli Li, Yasai Ji, Gaoyang Han, Xiaoran Li, Zhirui Fan, Yaqing Li, Yali Zhong, Jing Cao, Jing Zhao, Mingzhi Zhang, Jianguo Wen, Mariusz Adam Goscinski, Jahn M Nesland, Zhenhe Suo
BACKGROUND: Cancer cells exhibit an altered metabolism, which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) play a bottleneck role by transporting pyruvate into mitochondrial through the mitochondrial inner membrane. Therefore, their protein expression in cancers may be of clinical consequences. There are studies showing low levels of MPC1 expression in colon, kidney and lung cancers, and the expression of MPC1 correlates with poor prognosis...
November 16, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27835892/establishment-of-mitochondrial-pyruvate-carrier-1-mpc1-gene-knockout-mice-with-preliminary-gene-function-analyses
#10
Xiaoli Li, Yaqing Li, Gaoyang Han, Xiaoran Li, Yasai Ji, Zhirui Fan, Yali Zhong, Jing Cao, Jing Zhao, Goscinski Mariusz, Mingzhi Zhang, Jianguo Wen, Jahn M Nesland, Zhenhe Suo
Pyruvate plays a critical role in the mitochondrial tricarboxylic acid (TCA) cycle, and it is the center product for the synthesis of amino acids, carbohydrates and fatty acids. Pyruvate transported across the inner mitochondrial membrane appears to be essential in anabolic and catabolic intermediary metabolism. The mitochondrial pyruvate carrier (MPC) mounted in the inner membrane of mitochondria serves as the channel to facilitate pyruvate permeating. In mammals, the MPC is formed by two paralogous subunits, MPC1 and MPC2...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27707801/mitochondrial-carriers-link-the-catabolism-of-hydroxyaromatic-compounds-to-the-central-metabolism-in-candida-parapsilosis
#11
Igor Zeman, Martina Neboháčová, Gabriela Gérecová, Kornélia Katonová, Eva Jánošíková, Michaela Jakúbková, Ivana Centárová, Ivana Dunčková, L'ubomír Tomáška, Leszek P Pryszcz, Toni Gabaldón, Jozef Nosek
The pathogenic yeast Candida parapsilosis metabolizes hydroxyderivatives of benzene and benzoic acid to compounds channeled into central metabolism, including the mitochondrially localized tricarboxylic acid cycle, via the 3-oxoadipate and gentisate pathways. The orchestration of both catabolic pathways with mitochondrial metabolism as well as their evolutionary origin is not fully understood. Our results show that the enzymes involved in these two pathways operate in the cytoplasm with the exception of the mitochondrially targeted 3-oxoadipate CoA-transferase (Osc1p) and 3-oxoadipyl-CoA thiolase (Oct1p) catalyzing the last two reactions of the 3-oxoadipate pathway...
December 7, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27621446/e4f1-controls-a-transcriptional-program-essential-for-pyruvate-dehydrogenase-activity
#12
Matthieu Lacroix, Geneviève Rodier, Olivier Kirsh, Thibault Houles, Hélène Delpech, Berfin Seyran, Laurie Gayte, Francois Casas, Laurence Pessemesse, Maud Heuillet, Floriant Bellvert, Jean-Charles Portais, Charlene Berthet, Florence Bernex, Michele Brivet, Audrey Boutron, Laurent Le Cam, Claude Sardet
The mitochondrial pyruvate dehydrogenase (PDH) complex (PDC) acts as a central metabolic node that mediates pyruvate oxidation and fuels the tricarboxylic acid cycle to meet energy demand. Here, we reveal another level of regulation of the pyruvate oxidation pathway in mammals implicating the E4 transcription factor 1 (E4F1). E4F1 controls a set of four genes [dihydrolipoamide acetlytransferase (Dlat), dihydrolipoyl dehydrogenase (Dld), mitochondrial pyruvate carrier 1 (Mpc1), and solute carrier family 25 member 19 (Slc25a19)] involved in pyruvate oxidation and reported to be individually mutated in human metabolic syndromes...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27530892/a-simulation-study-on-the-constancy-of-cardiac-energy-metabolites-during-workload-transition
#13
Ryuta Saito, Ayako Takeuchi, Yukiko Himeno, Nobuya Inagaki, Satoshi Matsuoka
KEY POINTS: The cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant during physiological cardiac workload transition. How this is accomplished is not yet clarified, though Ca(2+) has been suggested to be one of the possible mechanisms. We constructed a detailed mathematical model of cardiac mitochondria based on experimental data and studied whether known Ca(2+) -dependent regulation mechanisms play roles in the metabolite constancy. Model simulations revealed that the Ca(2+) -dependent regulation mechanisms have important roles under the in vitro condition of isolated mitochondria where malate and glutamate were mitochondrial substrates, while they have only a minor role and the composition of substrates has marked influence on the metabolite constancy during workload transition under the simulated in vivo condition where many substrates exist...
December 1, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27497601/mechanism-of-antineoplastic-activity-of-lonidamine
#14
REVIEW
Kavindra Nath, Lili Guo, Bethany Nancolas, David S Nelson, Alexander A Shestov, Seung-Cheol Lee, Jeffrey Roman, Rong Zhou, Dennis B Leeper, Andrew P Halestrap, Ian A Blair, Jerry D Glickson
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC)...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27396958/mitochondrial-pyruvate-import-promotes-long-term-survival-of-antibody-secreting-plasma-cells
#15
Wing Y Lam, Amy M Becker, Krista M Kennerly, Rachel Wong, Jonathan D Curtis, Elizabeth M Llufrio, Kyle S McCommis, Johannes Fahrmann, Hannah A Pizzato, Ryan M Nunley, Jieun Lee, Michael J Wolfgang, Gary J Patti, Brian N Finck, Erika L Pearce, Deepta Bhattacharya
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs...
July 19, 2016: Immunity
https://www.readbyqxmd.com/read/27317664/mpc1-like-is-a-placental-mammal-specific-mitochondrial-pyruvate-carrier-subunit-expressed-in-postmeiotic-male-germ-cells
#16
Benoît Vanderperre, Kristina Cermakova, Jessica Escoffier, Mayis Kaba, Tom Bender, Serge Nef, Jean-Claude Martinou
Selective transport of pyruvate across the inner mitochondrial membrane by the mitochondrial pyruvate carrier (MPC) is a fundamental step that couples cytosolic and mitochondrial metabolism. The recent molecular identification of the MPC complex has revealed two interacting subunits, MPC1 and MPC2. Although in yeast, an additional subunit, MPC3, can functionally replace MPC2, no alternative MPC subunits have been described in higher eukaryotes. Here, we report for the first time the existence of a novel MPC subunit termed MPC1-like (MPC1L), which is present uniquely in placental mammals...
August 5, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27306203/severe-neonatal-presentation-of-mitochondrial-citrate-carrier-slc25a1-deficiency
#17
Amanda Smith, Skye McBride, Julien L Marcadier, Jean Michaud, Osama Y Al-Dirbashi, Jeremy Schwartzentruber, Chandree L Beaulieu, Sherri L Katz, Jacek Majewski, Dennis E Bulman, Michael T Geraghty, Mary-Ellen Harper, Pranesh Chakraborty, Matthew A Lines
Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984...
2016: JIMD Reports
https://www.readbyqxmd.com/read/27269731/mitochondrial-pyruvate-carrier-function-and-cancer-metabolism
#18
REVIEW
Adam J Rauckhorst, Eric B Taylor
Metabolic reprogramming in cancer supports the increased biosynthesis required for unchecked proliferation. Increased glucose utilization is a defining feature of many cancers that is accompanied by altered pyruvate partitioning and mitochondrial metabolism. Cancer cells also require mitochondrial tricarboxylic acid cycle activity and electron transport chain function for biosynthetic competency and proliferation. Recent evidence demonstrates that mitochondrial pyruvate carrier (MPC) function is abnormal in some cancers and that increasing MPC activity may decrease cancer proliferation...
June 2016: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/27225475/improvement-of-isobutanol-production-in-saccharomyces-cerevisiae-by-increasing-mitochondrial-import-of-pyruvate-through-mitochondrial-pyruvate-carrier
#19
Seong-Hee Park, Sujin Kim, Ji-Sook Hahn
Subcellular compartmentalization of the biosynthetic enzymes is one of the limiting factors for isobutanol production in Saccharomyces cerevisiae. Previously, it has been shown that mitochondrial compartmentalization of the biosynthetic pathway through re-locating cytosolic Ehrlich pathway enzymes into the mitochondria can increase isobutanol production. In this study, we improved mitochondrial isobutanol production by increasing mitochondrial pool of pyruvate, a key substrate for isobutanol production. Mitochondrial isobutanol biosynthetic pathway was introduced into bat1Δald6Δlpd1Δ strain, where genes involved in competing pathways were deleted, and MPC1, MPC2, and MPC3 genes encoding the subunits of mitochondrial pyruvate carrier (MPC) hetero-oligomeric complex were overexpressed with different combinations...
September 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27215380/requirement-for-the-mitochondrial-pyruvate-carrier-in-mammalian-development-revealed-by-a-hypomorphic-allelic-series
#20
Caitlyn E Bowman, Liang Zhao, Thomas Hartung, Michael J Wolfgang
Glucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse...
August 1, 2016: Molecular and Cellular Biology
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