title: Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function.
abstract: TLR-mediated activation of dendritic cells (DCs) is associated with a metabolic transition in which mitochondrial oxidative phosphorylation is inhibited by endogenously synthesized NO and the cells become committed to glucose and aerobic glycolysis for survival. We show that inhibition of mechanistic target of rapamycin (mTOR) extends the lifespan of TLR-activated DCs by inhibiting the induction of NO production, thereby allowing the cells to continue to use their mitochondria to generate ATP, and allowing them the flexibility to use fatty acids or glucose as nutrients to fuel core metabolism. These data provide novel mechanistic insights into how mTOR modulates DC metabolism and cellular longevity following TLR activation and provide an explanation for previous findings that mTOR inhibition enhances the efficacy of DCs in autologous vaccination.
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT 05405; Trudeau Institute, Saranac Lake, NY 12983; and.
authors.forename: Eyal
authors.initials: E
authors.lastname: Amiel
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Bart
authors.initials: B
authors.lastname: Everts
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT 05405;
authors.forename: Daniel
authors.initials: D
authors.lastname: Fritz
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT 05405;
authors.forename: Saritha
authors.initials: S
authors.lastname: Beauchamp
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT 05405;
authors.forename: Burong
authors.initials: B
authors.lastname: Ge
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Pearce
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 edwardpearce@path.wustl.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D014176:Protein Biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051193:Toll-Like Receptors / Q000276:immunology*; D014158:Transcription, Genetic; D014611:Vaccination
chemical_list: D005227:Fatty Acids; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
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