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  • 1
    Publication Date: 2013-03-29
    Description: Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1beta but not tumour-necrosis factor-alpha in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (gamma-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1alpha, an effect that is inhibited by 2-deoxyglucose, with interleukin-1beta as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1beta production during inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tannahill, G M -- Curtis, A M -- Adamik, J -- Palsson-McDermott, E M -- McGettrick, A F -- Goel, G -- Frezza, C -- Bernard, N J -- Kelly, B -- Foley, N H -- Zheng, L -- Gardet, A -- Tong, Z -- Jany, S S -- Corr, S C -- Haneklaus, M -- Caffrey, B E -- Pierce, K -- Walmsley, S -- Beasley, F C -- Cummins, E -- Nizet, V -- Whyte, M -- Taylor, C T -- Lin, H -- Masters, S L -- Gottlieb, E -- Kelly, V P -- Clish, C -- Auron, P E -- Xavier, R J -- O'Neill, L A J -- 098516/Wellcome Trust/United Kingdom -- R01 AI093451/AI/NIAID NIH HHS/ -- R56 AI090863/AI/NIAID NIH HHS/ -- U54 AI057153/AI/NIAID NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Apr 11;496(7444):238-42. doi: 10.1038/nature11986. Epub 2013 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535595" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Citric Acid Cycle/drug effects ; Deoxyglucose/pharmacology ; Down-Regulation/drug effects ; Genes, Mitochondrial/drug effects/genetics ; Glutamine/metabolism ; Glycolysis/drug effects/genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Immunity, Innate/drug effects ; Inflammation/metabolism ; Interleukin-1beta/*biosynthesis/genetics ; Lipopolysaccharides/pharmacology ; Macrophages/cytology/drug effects/metabolism ; Mice ; *Signal Transduction ; Succinic Acid/*metabolism ; Up-Regulation/drug effects ; gamma-Aminobutyric Acid/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-02-26
    Description: The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) 〉 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780242/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kerr, Emma M -- Gaude, Edoardo -- Turrell, Frances K -- Frezza, Christian -- Martins, Carla P -- MC_UU_12022/4/Medical Research Council/United Kingdom -- MC_UU_12022/6/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):110-3. doi: 10.1038/nature16967. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909577" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic/drug effects/genetics/metabolism/pathology ; Citric Acid Cycle ; DNA Copy Number Variations/*genetics ; Disease Progression ; Female ; Fibroblasts/metabolism ; Genes, ras/*genetics ; Genotype ; Glucose/*metabolism ; Glutathione/biosynthesis/metabolism ; *Glycolysis ; Lung Neoplasms/*drug therapy/genetics/*metabolism/pathology ; Male ; Mice ; Mutation/*genetics ; Oxidation-Reduction ; Phenotype ; Prognosis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-08-19
    Description: Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frezza, Christian -- Zheng, Liang -- Folger, Ori -- Rajagopalan, Kartik N -- MacKenzie, Elaine D -- Jerby, Livnat -- Micaroni, Massimo -- Chaneton, Barbara -- Adam, Julie -- Hedley, Ann -- Kalna, Gabriela -- Tomlinson, Ian P M -- Pollard, Patrick J -- Watson, Dave G -- Deberardinis, Ralph J -- Shlomi, Tomer -- Ruppin, Eytan -- Gottlieb, Eyal -- 090532/Wellcome Trust/United Kingdom -- DK072565-05/DK/NIDDK NIH HHS/ -- WT091112MA/Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Aug 17;477(7363):225-8. doi: 10.1038/nature10363.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21849978" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bilirubin/metabolism ; Cell Line ; Cells, Cultured ; Citric Acid Cycle ; Computer Simulation ; Fumarate Hydratase/deficiency/*genetics/*metabolism ; Fumarates/metabolism ; Genes, Lethal/*genetics ; *Genes, Tumor Suppressor ; Glutamine/metabolism ; Heme/metabolism ; Heme Oxygenase (Decyclizing)/antagonists & inhibitors/*genetics/*metabolism ; Kidney Neoplasms/drug therapy/enzymology/genetics/metabolism ; Leiomyomatosis/congenital/drug therapy/enzymology/genetics/metabolism ; Mice ; Mitochondria/metabolism ; Mutation/*genetics ; NAD/metabolism ; Neoplastic Syndromes, Hereditary ; Skin Neoplasms ; Uterine Neoplasms
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-10-16
    Description: Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894725/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894725/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chaneton, Barbara -- Hillmann, Petra -- Zheng, Liang -- Martin, Agnes C L -- Maddocks, Oliver D K -- Chokkathukalam, Achuthanunni -- Coyle, Joseph E -- Jankevics, Andris -- Holding, Finn P -- Vousden, Karen H -- Frezza, Christian -- O'Reilly, Marc -- Gottlieb, Eyal -- A12477/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Nov 15;491(7424):458-62. doi: 10.1038/nature11540. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064226" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Proliferation ; Enzyme Activation/drug effects ; Enzyme Activators/pharmacology ; Glucose/metabolism ; Glycine/metabolism/pharmacology ; Humans ; *Ligands ; Pyruvate Kinase/genetics/*metabolism ; Pyruvic Acid/metabolism ; Recombinant Proteins/metabolism ; Serine/*metabolism/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2014-11-11
    Description: Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255242/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Pell, Victoria R -- Gaude, Edoardo -- Aksentijevic, Dunja -- Sundier, Stephanie Y -- Robb, Ellen L -- Logan, Angela -- Nadtochiy, Sergiy M -- Ord, Emily N J -- Smith, Anthony C -- Eyassu, Filmon -- Shirley, Rachel -- Hu, Chou-Hui -- Dare, Anna J -- James, Andrew M -- Rogatti, Sebastian -- Hartley, Richard C -- Eaton, Simon -- Costa, Ana S H -- Brookes, Paul S -- Davidson, Sean M -- Duchen, Michael R -- Saeb-Parsy, Kourosh -- Shattock, Michael J -- Robinson, Alan J -- Work, Lorraine M -- Frezza, Christian -- Krieg, Thomas -- Murphy, Michael P -- G1100562/Medical Research Council/United Kingdom -- MC_U105663142/Medical Research Council/United Kingdom -- MC_U105674181/Medical Research Council/United Kingdom -- MC_UP_1101/3/Medical Research Council/United Kingdom -- MC_UU_12022/6/Medical Research Council/United Kingdom -- PG/07/126/24223/British Heart Foundation/United Kingdom -- PG/12/42/29655/British Heart Foundation/United Kingdom -- R01 HL071158/HL/NHLBI NIH HHS/ -- RG/12/4/29426/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Nov 20;515(7527):431-5. doi: 10.1038/nature13909. Epub 2014 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK [2] Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. ; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. ; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK. ; King's College London, British Heart Foundation Centre of Research Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. ; Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. ; Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA. ; Institute of Cardiovascular &Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. ; School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK. ; Unit of Paediatric Surgery, UCL Institute of Child Health, London WC1N 1EH, UK. ; Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK. ; University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383517" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/metabolism ; Animals ; Aspartic Acid/metabolism ; Citric Acid Cycle ; Disease Models, Animal ; Electron Transport ; Electron Transport Complex I/metabolism ; Fumarates/metabolism ; Ischemia/enzymology/*metabolism ; Malates/metabolism ; Male ; Metabolomics ; Mice ; Mitochondria/enzymology/*metabolism ; Myocardial Infarction/enzymology/metabolism ; Myocardium/cytology/enzymology/metabolism ; Myocytes, Cardiac/enzymology/metabolism ; NAD/metabolism ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/enzymology/*metabolism ; Stroke/enzymology/metabolism ; Succinate Dehydrogenase/metabolism ; Succinic Acid/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2016-09-20
    Description: Mitochondrial diseases are frequently associated with mutations in mitochondrial DNA (mtDNA). In most cases, mutant and wild-type mtDNAs coexist, resulting in heteroplasmy. The selective elimination of mutant mtDNA, and consequent enrichment of wild-type mtDNA, can rescue pathological phenotypes in heteroplasmic cells. Use of the mitochondrially targeted zinc finger-nuclease (mtZFN) results in degradation of mutant mtDNA through site-specific DNA cleavage. Here, we describe a substantial enhancement of our previous mtZFN-based approaches to targeting mtDNA, allowing near-complete directional shifts of mtDNA heteroplasmy, either by iterative treatment or through finely controlled expression of mtZFN, which limits off-target catalysis and undesired mtDNA copy number depletion. To demonstrate the utility of this improved approach, we generated an isogenic distribution of heteroplasmic cells with variable mtDNA mutant level from the same parental source without clonal selection. Analysis of these populations demonstrated an altered metabolic signature in cells harbouring decreased levels of mutant m.8993T〉G mtDNA, associated with neuropathy, ataxia, and retinitis pigmentosa (NARP). We conclude that mtZFN-based approaches offer means for mtDNA heteroplasmy manipulation in basic research, and may provide a strategy for therapeutic intervention in selected mitochondrial diseases.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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