Invited Speaker 12th International Meeting on AMPK 2023

Cellular homeostasis is maintained by AMPK-mediated metabolic cycles in mammalian cells. (#7)

John Albeck 1
  1. University of California, Davis, Davis, CA, United States

Cellular energetic status is balanced by a regulatory network centered on the kinases mTOR and AMPK, which are integrated with growth factor signaling pathways including RAS/ERK and PI3K/AKT. To understand how individual cells maintain energetic homeostasis,we used multiplexed live-cell imaging of biosensors for AMPK, AKT, ERK and other kinases, and for metabolites including ATP, ADP, NADH, and fructose 1,6-bisphosphate (FBP). These experiments revealed distinct dynamic behaviors occurring in individual cells that are not detectable at the cell population level. Under high levels of metabolic stress induced by inhibition of oxidative phosphorylation (OXPHOS),we observed tightly coordinated oscillations in the activities of AMPK, other kinases, and metabolites such as FBP. These oscillations occur with a period of 3-5 hours and appear to result from changes in glycolytic flux.Under more mild metabolic stress such as insulin withdrawal, we observe more relaxed fluctuations in AMPK activity that are intermittently coordinated with growth factor kinase signaling. We also find that individual cells transition through phases of metabolic activity that vary in their dependence on OXPHOS relative to glycolysis. Together these results reveal the existence of autonomous metabolic cycles that are not directly linked to the cell cycle, circadian rhythms, or other known cycles. We conclude that cellular energetic homeostasis is maintained by temporal organization of catabolic and anabolic activity, which provides a logical mechanism to integrate growth factor signaling and nutrient processing.We are currently investigating the mechanisms driving these cycles and how disruption of intracellular metabolic rhythms may contribute to cellular dysfunction under pathological conditions.