Laboratoire Matière et Systèmes Complexes

Gilles Charvin

Institut de génétique et de biologie moléculaire et cellulaire

Illkirch

Cellular mithridatism : a dynamical study of adaptation to oxidative poisoning in yeast

Youlian Goulev*, Michel Toledano#, Gilles Charvin*

* : IGBMC, Illkirch, # : CEA, Saclay

Homeostatic systems, which are ubiquitous in biology, are essential to maintain cellular physiological parameters within acceptable range regardless of the variations in the environment. Unicellulars, such as yeast, have evolved numerous specific mechanisms to counteract the stress induced by changes in the external medium (osmolarity, glucose level, light, heat, etc…). Whereas these defense mechanisms are well described at the molecular level by now, their integration into functional homeostatic systems remains poorly understood.

In this context, we have used the response to oxidative stress in Saccharomyces cerevisiae as a model to understand the link between the architecture of the stress sensing pathway and its adaptive properties. To this end, we have combined microfluidics-based assays and time-lapse microscopy to quantitatively monitor the cellular behaviour in response to temporally-controlled exposures to hydrogen peroxide (H2O2) stress patterns in single dividing cells.

Using cell growth rate as well as specific fluorescent markers of the response to oxidative stress, we first observed that cells display a perfect adaptation up to a critical H2O2 concentration, beyond which they quickly die. We have shown that the perfect adaptation can be simply explained by an “integral feedback” loop ensured by the H2O2-dependent expression of antioxidants enzymes. Strikingly, however, this model also predicted that cells should adapt to very high doses of H2O2, provided that the kinetics of input stress is slow enough. Using linear ramps of H2O2 level, we confirmed this prediction experimentally and identified the peroxiredoxin Tsa1, Tsa2 and Ahp1 as the main determinants of this non-intuitive behaviour. Last, we demonstrated that the same framework could be used to understand the mechanism of acquisition of tolerance to stress, which has long been reported but remained unexplained.

This study provides a comprehensive analysis of the response to oxidative stress in yeast, in which the multifaceted adaptive properties can be reconciled using a unique theoretical description. Therefore, it underlines the necessity of a quantitative and integrative approach to explain the emergence of homeostatic properties in living systems.