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Mitochondrial pyruvate carrier

Igor Zeman, Martina Neboháčová, Gabriela Gérecová, Kornélia Katonová, Eva Jánošiková, Michaela Jakúbková, Ivana Centárová, Ivana Dunčková, Ĺubomir 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...
October 5, 2016: G3: Genes—Genomes—Genetics
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
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...
August 17, 2016: Journal of Physiology
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)...
August 4, 2016: Biochimica et Biophysica Acta
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
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
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...
June 16, 2016: JIMD Reports
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 4, 2016: Current Opinion in Genetics & Development
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
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
Benoît Vanderperre, Sébastien Herzig, Petra Krznar, Manuel Hörl, Zeinab Ammar, Sylvie Montessuit, Sandra Pierredon, Nicola Zamboni, Jean-Claude Martinou
Mitochondrial import of pyruvate by the mitochondrial pyruvate carrier (MPC) is a central step which links cytosolic and mitochondrial intermediary metabolism. To investigate the role of the MPC in mammalian physiology and development, we generated a mouse strain with complete loss of MPC1 expression. This resulted in embryonic lethality at around E13.5. Mouse embryonic fibroblasts (MEFs) derived from mutant mice displayed defective pyruvate-driven respiration as well as perturbed metabolic profiles, and both defects could be restored by reexpression of MPC1...
May 2016: PLoS Genetics
Tsuyoshi Furumoto
Pyruvate is a central metabolite that must be imported into organelles for specific metabolic processes, including C4 photosynthesis. Plastidial and mitochondrial pyruvate transporter molecules were recently identified: the former was found based on C4 photosynthesis transcriptome analysis and the latter using a bioinformatics approach in yeast. The transport activities of these molecules were recently investigated in heterologous expression systems: Escherichia coli and Lactococcus lactis, respectively. These studies demonstrated the important roles of the NHD1/Bass2-protein coupling function and the mitochondria pyruvate carrier protein complex in pyruvate uptake...
June 2016: Current Opinion in Plant Biology
Jieun Choi, Eunjin Koh, Yu Shin Lee, Hyun-Woo Lee, Hyeok Gu Kang, Young Eun Yoon, Woong Kyu Han, Kyung Hwa Choi, Kyung-Sup Kim
Clear cell renal carcinoma (RCC), the most common malignancy arising in the adult kidney, exhibits increased aerobic glycolysis and low mitochondrial respiration due to von Hippel-Lindau gene defects and constitutive hypoxia-inducible factor-α expression. Sirt3 is a major mitochondrial deacetylase that mediates various types of energy metabolism. However, the role of Sirt3 as a tumor suppressor or oncogene in cancer depends on cell types. We show increased Sirt3 expression in the mitochondrial fraction of human RCC tissues...
June 3, 2016: Biochemical and Biophysical Research Communications
David Vaughan, Michael Brogioli, Thomas Maier, Andy White, Sarah Waldron, Jörn Rittweger, Marco Toigo, Jessica Wettstein, Endre Laczko, Martin Flück
OBJECTIVE: A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle...
2016: PloS One
Thierry Brun, Pierre Maechler
Mitochondria play a central role in pancreatic beta-cells by coupling metabolism of the secretagogue glucose to distal events of regulated insulin exocytosis. This process requires transports of both metabolites and nucleotides in and out of the mitochondria. The molecular identification of mitochondrial carriers and their respective contribution to beta-cell function have been uncovered only recently. In type 2 diabetes, mitochondrial dysfunction is an early event and may precipitate beta-cell loss. Under diabetogenic conditions, characterized by glucotoxicity and lipotoxicity, the expression profile of mitochondrial carriers is selectively modified...
October 2016: Biochimica et Biophysica Acta
Leiming Wang, Mafei Xu, Jun Qin, Shih-Chieh Lin, Hui-Ju Lee, Sophia Y Tsai, Ming-Jer Tsai
Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as a critical regulator of glycolysis in prostate cancer cells, which in turn controls cancer cell growth, invasion, and the tumorigenic capability...
March 22, 2016: Oncotarget
P Jourdain, I Allaman, K Rothenfusser, H Fiumelli, P Marquet, P J Magistretti
Converging experimental data indicate a neuroprotective action of L-Lactate. Using Digital Holographic Microscopy, we observe that transient application of glutamate (100 μM; 2 min) elicits a NMDA-dependent death in 65% of mouse cortical neurons in culture. In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%. UK5099, a blocker of the Mitochondrial Pyruvate Carrier, fully prevents L-Lactate-mediated neuroprotection. In addition, L-Lactate-induced neuroprotection is not only inhibited by probenicid and carbenoxolone, two blockers of ATP channel pannexins, but also abolished by apyrase, an enzyme degrading ATP, suggesting that ATP produced by the Lactate/Pyruvate pathway is released to act on purinergic receptors in an autocrine/paracrine manner...
2016: Scientific Reports
Ina Aretz, Christopher Hardt, Ilka Wittig, David Meierhofer
Hundreds of genes have been associated with respiratory chain disease (RCD), the most common inborn error of metabolism so far. Elimination of the respiratory electron chain by depleting the entire mitochondrial DNA (mtDNA, ρ(0) cells) has therefore one of the most severe impacts on the energy metabolism in eukaryotic cells. In this study, proteomic data sets including the post-translational modifications (PTMs) phosphorylation and ubiquitination were integrated with metabolomic data sets and selected enzyme activities in the osteosarcoma cell line 143B...
May 2016: Molecular & Cellular Proteomics: MCP
Bethany Nancolas, Lili Guo, Rong Zhou, Kavindra Nath, David S Nelson, Dennis B Leeper, Ian A Blair, Jerry D Glickson, Andrew P Halestrap
Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitizing tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibit 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)...
April 1, 2016: Biochemical Journal
Lawrence R Gray, Adam J Rauckhorst, Eric B Taylor
The discovery that theMPC1andMPC2genes encode the protein components of the mitochondrial pyruvate carrier (MPC) has invigorated studies of mitochondrial pyruvate transport and its regulation in normal and disease states. Indeed, recent reports have demonstrated MPC involvement in the control of cell fate in cancer and gluconeogenesis in models of type 2 diabetes. Biochemical measurements of MPC activity are foundational for understanding the role of pyruvate transport in health and disease. We developed a 96-well scaled method of [(14)C]pyruvate uptake that markedly decreases sample requirements and increases throughput relative to previous techniques...
April 1, 2016: Journal of Biological Chemistry
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