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The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism.
Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK, McAtee-Pereira AG, Guo Y, Trenary I, Hernandez A, Fults JB, Williams DL, Sherwood ER, Bohannon JK
(2018) J Immunol 200: 3777-3789
MeSH Terms: Adenosine Triphosphate, Animals, Candida albicans, Candidiasis, Glycolysis, Lipid A, Macrophages, Male, Mice, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, Signal Transduction, Staphylococcal Infections, Staphylococcus aureus, TOR Serine-Threonine Kinases, Toll-Like Receptor 4
Show Abstract · Added March 28, 2019
Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with and that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.
Copyright © 2018 by The American Association of Immunologists, Inc.
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16 MeSH Terms
Regional differences in brain glucose metabolism determined by imaging mass spectrometry.
Kleinridders A, Ferris HA, Reyzer ML, Rath M, Soto M, Manier ML, Spraggins J, Yang Z, Stanton RC, Caprioli RM, Kahn CR
(2018) Mol Metab 12: 113-121
MeSH Terms: Adenosine Triphosphate, Animals, Basal Metabolism, Brain, Fasting, Glucose, Glycolysis, Male, Mass Spectrometry, Mice, Mice, Inbred C57BL, Organ Specificity, Pentose Phosphate Pathway
Show Abstract · Added March 26, 2019
OBJECTIVE - Glucose is the major energy substrate of the brain and crucial for normal brain function. In diabetes, the brain is subject to episodes of hypo- and hyperglycemia resulting in acute outcomes ranging from confusion to seizures, while chronic metabolic dysregulation puts patients at increased risk for depression and Alzheimer's disease. In the present study, we aimed to determine how glucose is metabolized in different regions of the brain using imaging mass spectrometry (IMS).
METHODS - To examine the relative abundance of glucose and other metabolites in the brain, mouse brain sections were subjected to imaging mass spectrometry at a resolution of 100 μm. This was correlated with immunohistochemistry, qPCR, western blotting and enzyme assays of dissected brain regions to determine the relative contributions of the glycolytic and pentose phosphate pathways to regional glucose metabolism.
RESULTS - In brain, there are significant regional differences in glucose metabolism, with low levels of hexose bisphosphate (a glycolytic intermediate) and high levels of the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolite hexose phosphate in thalamus compared to cortex. The ratio of ATP to ADP is significantly higher in white matter tracts, such as corpus callosum, compared to less myelinated areas. While the brain is able to maintain normal ratios of hexose phosphate, hexose bisphosphate, ATP, and ADP during fasting, fasting causes a large increase in cortical and hippocampal lactate.
CONCLUSION - These data demonstrate the importance of direct measurement of metabolic intermediates to determine regional differences in brain glucose metabolism and illustrate the strength of imaging mass spectrometry for investigating the impact of changing metabolic states on brain function at a regional level with high resolution.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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13 MeSH Terms
Introduction to the Thematic Minireview Series: Brain glycogen metabolism.
Carlson GM, Dienel GA, Colbran RJ
(2018) J Biol Chem 293: 7087-7088
MeSH Terms: Brain, Glycogen, Glycogenolysis, Glycolysis, Humans, Review Literature as Topic, Synaptic Transmission
Show Abstract · Added March 21, 2018
The synthesis of glycogen allows for efficient intracellular storage of glucose molecules in a soluble form that can be rapidly released to enter glycolysis in response to energy demand. Intensive studies of glucose and glycogen metabolism, predominantly in skeletal muscle and liver, have produced innumerable insights into the mechanisms of hormone action, resulting in the award of several Nobel Prizes over the last one hundred years. Glycogen is actually present in all cells and tissues, albeit at much lower levels than found in muscle or liver. However, metabolic and physiological roles of glycogen in other tissues are poorly understood. This series of Minireviews summarizes what is known about the enzymes involved in brain glycogen metabolism and studies that have linked glycogen metabolism to multiple brain functions involving metabolic communication between astrocytes and neurons. Recent studies unexpectedly linking some forms of epilepsy to mutations in two poorly understood proteins involved in glycogen metabolism are also reviewed.
© 2018 Carlson et al.
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7 MeSH Terms
Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.
Warren EB, Aicher AE, Fessel JP, Konradi C
(2017) PLoS One 12: e0190456
MeSH Terms: Animals, Cells, Cultured, Corpus Striatum, Creatine Kinase, DNA, Mitochondrial, Energy Metabolism, Ethidium, Glycolysis, Humans, Mitochondria, Oxygen Consumption, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 14, 2018
Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.
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13 MeSH Terms
The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.
Burmeister MA, Brown JD, Ayala JE, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
(2017) Am J Physiol Endocrinol Metab 313: E651-E662
MeSH Terms: Acetyl-CoA Carboxylase, Adenylate Kinase, Animals, Body Composition, CHO Cells, Cricetulus, Dose-Response Relationship, Drug, Eating, Exenatide, Food, Glucagon-Like Peptide-1 Receptor, Glycolysis, Homeostasis, Male, Mice, Mice, Inbred C57BL, Peptides, Sensation, TOR Serine-Threonine Kinases, Venoms, Ventromedial Hypothalamic Nucleus
Show Abstract · Added October 23, 2017
Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.
Copyright © 2017 the American Physiological Society.
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21 MeSH Terms
Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.
Hardeman KN, Peng C, Paudel BB, Meyer CT, Luong T, Tyson DR, Young JD, Quaranta V, Fessel JP
(2017) Sci Rep 7: 42604
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Drug Resistance, Neoplasm, Glucose, Glycolysis, Humans, Indoles, Melanoma, Molecular Targeted Therapy, Mutation, Oncogenes, Pharmacogenomic Variants, Phenotype, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides, Treatment Outcome
Show Abstract · Added April 18, 2017
Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.
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17 MeSH Terms
AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.
Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, Macintyre AN, Goraksha-Hicks P, de Cubas AA, Liu T, Warmoes MO, Abel ED, Yeoh AE, Gershon TR, Rathmell WK, Richards KL, Locasale JW, Rathmell JC
(2016) Cell Metab 23: 649-62
MeSH Terms: AMP-Activated Protein Kinases, Animals, Cell Line, Tumor, Cell Survival, Glycolysis, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Inbred C57BL, Mitochondria, Multiprotein Complexes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Notch, Signal Transduction, Stress, Physiological, T-Lymphocytes, TOR Serine-Threonine Kinases
Show Abstract · Added August 8, 2016
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.
Kishi S, Campanholle G, Gohil VM, Perocchi F, Brooks CR, Morizane R, Sabbisetti V, Ichimura T, Mootha VK, Bonventre JV
(2015) EBioMedicine 2: 1090-101
MeSH Terms: Acute Kidney Injury, Adenosine Triphosphate, Animals, Cell Respiration, Cytochromes c, Deoxyglucose, Disease Models, Animal, Epithelial Cells, Ethanolamines, Galactose, Glycolysis, Humans, Inflammation, Ischemic Preconditioning, Kidney, Kidney Tubules, L-Lactate Dehydrogenase, LLC-PK1 Cells, Male, Meclizine, Mice, Inbred C57BL, Mitochondria, Protective Agents, Reperfusion Injury, Sodium Cyanide, Swine, Up-Regulation
Show Abstract · Added September 12, 2016
Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.
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27 MeSH Terms
Glycolytic enzymes localize to ribonucleoprotein granules in Drosophila germ cells, bind Tudor and protect from transposable elements.
Gao M, Thomson TC, Creed TM, Tu S, Loganathan SN, Jackson CA, McCluskey P, Lin Y, Collier SE, Weng Z, Lasko P, Ohi MD, Arkov AL
(2015) EMBO Rep 16: 379-86
MeSH Terms: Animals, Animals, Genetically Modified, Base Sequence, Cytoplasmic Granules, DNA Transposable Elements, Drosophila, Drosophila Proteins, Germ Cells, Glycolysis, Membrane Transport Proteins, MicroRNAs, Molecular Sequence Data, Ribonucleoproteins, Sequence Analysis, DNA
Show Abstract · Added January 5, 2016
Germ cells give rise to all cell lineages in the next-generation and are responsible for the continuity of life. In a variety of organisms, germ cells and stem cells contain large ribonucleoprotein granules. Although these particles were discovered more than 100 years ago, their assembly and functions are not well understood. Here we report that glycolytic enzymes are components of these granules in Drosophila germ cells and both their mRNAs and the enzymes themselves are enriched in germ cells. We show that these enzymes are specifically required for germ cell development and that they protect their genomes from transposable elements, providing the first link between metabolism and transposon silencing. We further demonstrate that in the granules, glycolytic enzymes associate with the evolutionarily conserved Tudor protein. Our biochemical and single-particle EM structural analyses of purified Tudor show a flexible molecule and suggest a mechanism for the recruitment of glycolytic enzymes to the granules. Our data indicate that germ cells, similarly to stem cells and tumor cells, might prefer to produce energy through the glycolytic pathway, thus linking a particular metabolism to pluripotency.
© 2015 The Authors.
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14 MeSH Terms
Metabolomics of ADSOL (AS-1) red blood cell storage.
Roback JD, Josephson CD, Waller EK, Newman JL, Karatela S, Uppal K, Jones DP, Zimring JC, Dumont LJ
(2014) Transfus Med Rev 28: 41-55
MeSH Terms: Adenine, Animals, Blood Preservation, Cell Membrane, Chromatography, Liquid, Erythrocyte Transfusion, Erythrocytes, Gas Chromatography-Mass Spectrometry, Glucose, Glycolysis, Humans, Kinetics, Lipids, Mannitol, Metabolome, Mice, Mice, Inbred C57BL, Oxidative Stress, Signal Transduction, Sodium Chloride, Tandem Mass Spectrometry
Show Abstract · Added March 20, 2014
Population-based investigations suggest that red blood cells (RBCs) are therapeutically effective when collected, processed, and stored for up to 42 days under validated conditions before transfusion. However, some retrospective clinical studies have shown worse patient outcomes when transfused RBCs have been stored for the longest times. Furthermore, studies of RBC persistence in the circulation after transfusion have suggested that considerable donor-to-donor variability exists and may affect transfusion efficacy. To understand the limitations of current blood storage technologies and to develop approaches to improve RBC storage and transfusion efficacy, we investigated the global metabolic alterations that occur when RBCs are stored in AS-1 (AS1-RBC). Leukoreduced AS1-RBC units prepared from 9 volunteer research donors (12 total donated units) were serially sampled for metabolomics analysis over 42 days of refrigerated storage. Samples were tested by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, and specific biochemical compounds were identified by comparison to a library of purified standards. Over 3 experiments, 185 to 264 defined metabolites were quantified in stored RBC samples. Kinetic changes in these biochemicals confirmed known alterations in glycolysis and other pathways previously identified in RBCs stored in saline, adenine, glucose and mannitol solution (SAGM-RBC). Furthermore, we identified additional alterations not previously seen in SAGM-RBCs (eg, stable pentose phosphate pathway flux, progressive decreases in oxidized glutathione), and we delineated changes occurring in other metabolic pathways not previously studied (eg, S-adenosyl methionine cycle). These data are presented in the context of a detailed comparison with previous studies of SAGM-RBCs from human donors and murine AS1-RBCs. Global metabolic profiling of AS1-RBCs revealed a number of biochemical alterations in stored blood that may affect RBC viability during storage as well as therapeutic effectiveness of stored RBCs in transfusion recipients. These results provide future opportunities to more clearly pinpoint the metabolic defects during RBC storage, to identify biomarkers for donor screening and prerelease RBC testing, and to develop improved RBC storage solutions and methodologies.
Copyright © 2014 Elsevier Inc. All rights reserved.
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21 MeSH Terms