title: FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells.
abstract: Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the long-term proliferative capacity of neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3-regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways. Characterization of the metabolic circuit observed upon loss of FoxO3 revealed a drop in glutaminolysis and filling of the tricarboxylic acid (TCA) cycle. Additionally, we found that glucose uptake, glucose metabolism and oxidative pentose phosphate pathway activity were similarly repressed in the absence of FoxO3. Finally, we demonstrate that impaired glucose and glutamine metabolism compromises the proliferative potential of NPCs and that this is exacerbated following FoxO3 loss. Collectively, our findings show that a FoxO3-dependent metabolic programme supports redox balance and the neurogenic potential of NPCs.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York City, NY, USA.
authors.forename: Hyeonju
authors.initials: H
authors.lastname: Yeo
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051379:Mice; D008822:Mice, Transgenic; D009249:NADP / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D017382:Reactive Oxygen Species; D005973:Glutamine; D009249:NADP; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose