Journal
EMBO JOURNAL
Volume 32, Issue 19, Pages 2589-2602Publisher
WILEY
DOI: 10.1038/emboj.2013.186
Keywords
FoxO3; glutaminolysis; oxidative stress; pentose phosphate pathway
Categories
Funding
- Weill Cornell Medical College
- Ellison Medical Foundation [AG-NS-0646-10]
- Sidney Kimmel foundation [SKF-092]
- Damon Runyon Cancer Research Foundation [DRG-2056-10]
- National Institutes of Health [5P01CA120964-05]
- Dana-Farber/Harvard Cancer Center [5P30CA006516-46]
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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.
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