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

We 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 (H(2) O(2)), 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 H(2) O(2) 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 H(2) O(2) concentration level. Actually, the impact of the membrane upon the H(2) O(2) stress felt by the cell is greater when micromolar H(2) O(2) is present (9-fold less H(2) O(2) in the cell than out of the cell) than when millimolar H(2) O(2) is present (about 2-fold less H(2) O(2) in the cell than out of the cell). The ratio between maximal external H(2) O(2) and internal H(2) O(2) concentration also changes, reducing from 8 to 2 while external H(2) O(2) 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 H(2) O(2) maximal concentration, which surprisingly does not depend on cell density. The external H(2) O(2) half-life and the cumulative internal H(2) O(2) exposure do depend upon cell density. Based on these analyses and in order to introduce a concept of dose response relationship for H(2) O(2)-induced cell death, we developed the concepts of “maximal internal H(2) O(2) concentration” and “cumulative internal H(2) O(2) concentration” (e.g. the total amount of H(2) O(2)). We predict that cumulative internal H(2) O(2) concentration is responsible for the H(2) O(2)-mediated death of bacterial cells.