Eukaryotic metabolism as an autonomous oscillator driving the cell through the cell cycle
Pr Matthias HEINEMANN
Faculty of science and engineering, University of Groningen, Netherlands
Friday, February 28th 2020 - 11 a.m.
- Auditorium, IGBMC
Hosted by Development and stem cells, Gilles CHARVIN
The eukaryotic cell division is thought to be controlled the cyclin dependent kinase (CDK) machinery. However, the fact that CDKs came late in the evolution, and the fact that oscillations in global transcription and certain cell cycle components were also found during cell cycle arrest, suggest that cell cycle regulators external to the cyclin/CDK machinery could exist. We hypothesized that a metabolic oscillator could represent such global cell cycle regulator.
Using microfluidics, single-cell metabolite and cell cycle reporters, we found that yeast metabolism is a CDK-independent oscillator, which orbits in synchrony with the cell cycle, but also in non-dividing cells. Using environmental perturbations and conditional protein depletion experiments, we found that the metabolic oscillator and the cyclin/CDK machinery form a system of coupled oscillators. Through analysis of our experimental data with a Kuramoto model, we unraveled the high-level topology of this coupled oscillator system. In this system, the metabolic oscillator independently controls the entry into the cell cycle and mitosis. We found that control of the cell cycle START is accomplished by a differential scaling in the protein synthesis and cell size dynamics during the G1 phase.
Overall, this work suggests that cell cycle control emerges as higher order function from coupled and mutually entrained oscillators, including the oscillating metabolism. Given the evolutionary conservation of metabolic pathways across life kingdoms, the metabolic oscillator may constitute an ancestral regulator of cell division.