A CDK-independent metabolic oscillator orchestrating the budding yeast cell cycle?
The eukaryotic cell division is thought to be controlled by periodic activity of the cyclin dependent kinase (CDK) machinery. However, the fact that CDKs came late in the evolution of eukaryotes, and the fact that oscillations in global transcription and the anaphase-promoting complex activity were also found in during cell cycle arrest, suggest that cell cycle regulators external to the cyclin/CDK machinery could exist. In the basis of previous indication, we hypothesized that an autonomous metabolic oscillator could represent such global cell cycle regulator.
Using microfluidics technology, in combination with single cell metabolite and cell cycle reporters, we found that yeast metabolism is a CDK-independent oscillator, which orbits across nutrients and at different metabolic modes, 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. In this system, the metabolic oscillator robustly gates the phase of the early and the late cell cycle, whereas a minimal metabolic frequency threshold must be reached for the cell cycle to START.
This work suggests that cell cycle control is not just the result of the cyclin/CDK machinery, but emerges as a 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.
Matthias Heinemann is full professor for molecular systems biology at the University of Groningen in the Netherlands. Matthias earned his PhD in engineering from the RWTH Aachen University in Germany and mutated into a biologist during his postdoc time at the Institute of Molecular Systems Biology (ETH Zurich). In his research, he aims to understand how primary carbon and energy metabolism functions and how it controls other cellular processes. To achieve this goal, the members of his lab use wet and dry lab approaches of systems biology, in combination with the more classical approaches to biological research, with a particular emphasis on zooming into metabolism of individual cells.
In recent years, his lab has found that cells can measure intracellular flux (i.e. the rate of metabolic activity) and use this information for regulation of other metabolic fluxes, opening up a new view on metabolism (Mol Sys Biol 2010, PNAS 2012). Further, the lab showed that such flux-sensing can lead to bistability in metabolism (Mol Sys Biol 2014), to antibiotic tolerant persisters (Mol Sys Biol 2016), and has relevance for aging in yeast (eLife 2015). Recently, the lab discovered that an upper limit in Gibbs energy dissipation rate governs cellular metabolism (Nat Metabolism 2018) and that metabolism of yeast is an autonomous oscillator (Mol Cell 2017).