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Mitochondrial pyruvate carrier

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https://www.readbyqxmd.com/read/28867301/nonalcoholic-fatty-liver-disease-as-a-nexus-of-metabolic-and-hepatic-diseases
#1
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...
August 29, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28812582/control-of-intestinal-stem-cell-function-and-proliferation-by-mitochondrial-pyruvate-metabolism
#2
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...
August 14, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28812580/lactate-dehydrogenase-activity-drives-hair-follicle-stem-cell-activation
#3
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...
August 14, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28624784/mitochondrial-pyruvate-carrier-function-determines-cell-stemness-and-metabolic-reprogramming-in-cancer-cells
#4
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
https://www.readbyqxmd.com/read/28597936/the-beneficial-metabolic-effects-of-insulin-sensitizers-are-not-attenuated-by-mitochondrial-pyruvate-carrier-2-hypomorphism
#5
Patrick A Vigueira, Kyle S McCommis, Wesley T Hodges, George G Schweitzer, Serena L Cole, Lalita Oonthonpan, Eric B Taylor, William G McDonald, Rolf F Kletzien, Jerry R Colca, Brian N Finck
What is the central question of this study? The antidiabetic effects of thiazolidinedione (TZD) drugs may be mediated in part by a molecular interaction with the constituent proteins of the mitochondrial pyruvate carrier complex (MPC1 and MPC2). We examined the ability of a mutant mouse strain expressing an N-terminal truncation of MPC2 (Mpc2Δ16 mice) to respond to TZD treatment. What is the main finding and its importance? The response of Mpc2Δ16 mice to TZD treatment was not significantly different from that of wild-type C57BL6/J control animals, suggesting that the 16 N-terminal amino acids of MPC2 are dispensable for the effects of TZD treatment...
June 9, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28522206/functional-properties-of-the-mitochondrial-carrier-system
#6
REVIEW
Eric B Taylor
The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53-member canonical SLC25A family and a lesser number of identified noncanonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function...
May 15, 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28462847/breaking-the-ritual-metabolic-cycle-in-order-to-save-acetyl-coa-a-potential-role-for-mitochondrial-humanin-in-t2-bladder-cancer-aggressiveness
#7
Nesreen Nabil Omar, Reham Fathy Tash, Youssef Shoukry, Karim Omar ElSaeed
INTRODUCTION: Cancer cells may exhibit outsourcing of their high energy need in order to avoid the intrinsic mitochondrial apoptosis. Reduced mitochondrial respiration and accumulation of mitochondrial genome mutations are among metabolic transformations in this regard. Mitochondrial humanin (MT-RNR2) is a small peptide with anti-apoptotic activities attributed to binding some pro-apoptotic proteins. AIM OF THE WORK: The current study aims at investigating the expression of mitochondrial humanin in bladder tumor cells and the possible casting of humanin anti-apoptotic action through orchestrating some of the mitochondrial metabolic enzymes...
April 24, 2017: Journal of the Egyptian National Cancer Institute
https://www.readbyqxmd.com/read/28397687/a-metabolic-switch-controls-intestinal-differentiation-downstream-of-adenomatous-polyposis-coli-apc
#8
Imelda T Sandoval, Richard Glenn C Delacruz, Braden N Miller, Shauna Hill, Kristofor A Olson, Ana E Gabriel, Kevin Boyd, Christeena Satterfield, Holly Van Remmen, Jared Rutter, David A Jones
Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1), a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation...
April 11, 2017: ELife
https://www.readbyqxmd.com/read/28370579/modulating-mitochondrial-pyruvate-carrier-a-promising-therapeutic-target-in-parkinson-s-disease
#9
Lorena Orgaz, Guillermo Bueno Gil
No abstract text is available yet for this article.
May 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28254829/inhibition-of-the-mitochondrial-pyruvate-carrier-protects-from-excitotoxic-neuronal-death
#10
Ajit S Divakaruni, Martina Wallace, Caodu Buren, Kelly Martyniuk, Alexander Y Andreyev, Edward Li, Jerel A Fields, Thekla Cordes, Ian J Reynolds, Brenda L Bloodgood, Lynn A Raymond, Christian M Metallo, Anne N Murphy
Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28154187/decreased-mitochondrial-pyruvate-transport-activity-in-the-diabetic-heart-role-of-mitochondrial-pyruvate-carrier-2-mpc2-acetylation
#11
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 hyperacetylated 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 hyperacetylation. Functionally, isolated Akita heart mitochondria have significantly impaired maximal (state 3) respiration with physiological pyruvate (0...
March 17, 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
#12
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 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...
May 2017: 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
#13
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
#14
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...
December 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
#15
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
#16
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...
March 2017: 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
#17
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
#18
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
#19
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
#20
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 29, 2016: Oncotarget
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