EAGER: An ultradian cycle that mediates metabolic homeostasis under extreme conditions

Oxidative phosphorylation (OXPHOS) provides the majority of free energy for most eukaryotic cells. Remarkably, inhibition of OXPHOS for extended periods of time is well tolerated by cells, through compensation by glycolysis. The systems-level properties that enable such metabolic adaptation are yet to be understood.

The PI previously observed a cycling of metabolism on inhibition of OXPHOS. This project investigates how cells manage their energy budget dynamically to withstand OXPHOS inhibition. By identifying these mechanisms, the project enables a range of future investigations that will establish the function and significance of metabolic cycling within physiological circumstances.

This project is developing an extracurricular program for undergraduates and high school students that introduces them to current research concepts in metabolic biochemistry, cell fate regulation, and dynamical systems modeling. Activities include reading and presentation of primary literature, construction of pathway maps using CellDesigner software, and contribution to the writing of reviews that will be submitted for publication or posted to public websites.

Students learn about the process of conducting research, and the applications of research findings to human or veterinary medicine and metabolic engineering.

Oxidative phosphorylation (OXPHOS) provides the majority of free energy for most eukaryotic cells. Remarkably, inhibition of OXPHOS for extended periods of time is well tolerated by cells when sufficient glucose and other nutrients are available. Mammalian cells can survive full OXPHOS inhibition and continue to proliferate, even though ATP generation per glucose molecule is reduced from approximately 36 to only 2.

Their survival is enabled by a seemingly seamless switch to glycolysis, which has largely been assumed to occur uniformly in time within all cells of a population. However, recent work from the PI’s lab has revealed, using live-cell biosensors, that OXPHOS inhibition induces large oscillations in the activity of AMPK, a key regulator of metabolic status.

Similar oscillations in AMPK activity occur in multiple cell types and have a characteristic period of about 3 hours, regardless of which mitochondrial complex is inhibited. This stereotypical pattern suggests the existence of a common temporal program, which has been termed the OXPHOS Inhibition-induced Cycle (OPIC). Furthermore, additional data show that the activity of AMPK, which stimulates catabolism, alternates with the activity of ERK and mTORC1, which are key pro-anabolic signaling pathways.

These data imply that metabolic homeostasis is temporally organized into phases dedicated to distinct metabolic processes. This project is undertaken to identify the network underlying cell cycle-independent, hours-scale periodicity in mammalian cellular metabolism. The mechanisms driving OPIC are examined by (1) disabling the cycle to determine its importance, (2) determining the functional role of the cycle in metabolism and (3) to identify the regulators and readouts of the cycle.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.