A Boolean probabilistic model of metabolic adaptation to oxygen in relation to iron homeostasis and oxidative stress

Using a methodology based on probabilistic Boolean modelling, we constructed the first model of yeast iron homeostasis including oxygen-related reactions in the frame of central metabolism. The resulting model of 642 elements and 1007 reactions was validated by comparing simulations with a large body of experimental results (147 phenotypes and 11 metabolic flux experiments). We removed every gene, thus generating in silico mutants. The simulations of the different mutants gave rise to a remarkably accurate qualitative description of most of the experimental phenotype (overall consistency > 91.5%). A second validation involved analysing the anaerobiosis to aerobiosis transition. Therefore, we compared the simulations of our model with different levels of oxygen to experimental metabolic flux data. The simulations reproducted accurately ten out of the eleven metabolic fluxes. We show here that our probabilistic Boolean modelling strategy provides a useful description of the dynamics of a complex biological system. A clustering analysis of the simulations of all in silico mutations led to the identification of clear phenotypic profiles, thus providing new insights into some metabolic response to stress conditions. Finally, the model was also used to explore several new hypothesis in order to better understand some unexpected phenotypes in given mutants.All these results show that this model, and the underlying modelling strategy, are powerful tools for improving our understanding of complex biological problems.A large body of data suggests that mitochondrial abnormalities may link gene defects and/or environmental challenges to many pathologies including several neurodegenerative processes (for reviews, see [1-4]). Mitochondria are essential organelles serving as the main site of oxygen use within cells. The divalent reduction of oxygen by the respiratory chain is tightly coupled to ATP synthesis by the oxidative phosphorylation machinery. However, a small proportion o