Hydrogen Peroxide Induced Cell Death: The Major Defences Relative Roles and Consequences in E-coli

International audienceWe recently developed a mathematical model for predicting reactive oxygen species (ROS) concentration and macromolecules oxidation in vivo. We constructed such a model using Escherichia coli as a model organism and a set of ordinary differential equations. In order to evaluate the major defences relative roles against hydrogen peroxide (H2O2), we investigated the relative contributions of the various reactions to the dynamic system and searched for approximate analytical solutions for the explicit expression of changes in H2O2 internal or external concentrations. Although the key actors in cell defence are enzymes and membrane, a detailed analysis shows that their involvement depends on the H2O2 concentration level. Actually, the impact of the membrane upon the H2O2 stress felt by the cell is greater when micromolar H2O2 is present (9-fold less H2O2 in the cell than out of the cell) than when millimolar H2O2 is present (about 2-fold less H2O2 in the cell than out of the cell). The ratio between maximal external H2O2 and internal H2O2 concentration also changes, reducing from 8 to 2 while external H2O2 concentration increases from micromolar to millimolar. This non-linear behaviour mainly occurs because of the switch in the predominant scavenger from Ahp (Alkyl Hydroperoxide Reductase) to Cat (catalase). The phenomenon changes the internal H2O2 maximal concentration, which surprisingly does not depend on cell density. The external H2O2 half-life and the cumulative internal H2O2 exposure do depend upon cell density. Based on these analyses and in order to introduce a concept of dose response relationship for H2O2-induced cell death, we developed the concepts of “maximal internal H2O2 concentration” and “cumulative internal H2O2 concentration” (e.g. the total amount of H2O2). We predict that cumulative internal H2O2 concentration is responsible for the H2O2-mediated death of bacterial cells