Staying alive: metabolic adaptations to quiescence

Abstract

Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. In some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the PI3Kinase/TOR signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOR kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. In this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems.

Figure 1. External factors induce cell growth and suppress autophagy via Akt and TOR. Upon stimulation by external factors, such as growth factors, the receptor tyrosine kinase is phosphorylated and recruits PI3K. PI3K phosphorylates PtdIns(4,5)P₂ to PtdIns(3,4,5)P₃, which then recruits PDK and Akt to the cell membrane. Akt, when phosphorylated by mTORC2 and PDK, inhibits TSC, which in turn inhibits Rheb. When activated, Rheb promotes mTORC1 action, which leads to an increase in biosynthesis and suppression of autophagy via ULK1. Thus, nutrient-rich conditions lead to high activity of PI3K, Akt, and mTORC1, while nutrient depletion causes reduced PI3K activity and a resulting decrease in mTORC1 activity.

Figure 2. Autophagy is activated by low mTOR signaling and activation of ULK1. In starvation conditions, high TSC activity represses mTOR, which allows ULK1 to become active. After recruiting additional proteins to form a complex, ULK1 promotes autophagosome formation and autophagy. In contrast, high mTOR activity in high-nutrient conditions phorphorylates ULK1 and suppresses the induction of autophagy.