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

Lionel Uhl,Sam Dukan,John Travers Hancock

doi:10.1371/journal.pone.0159706

Abstract

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 (H2 O2), 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 H2 O2 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 H2 O2 concentration level. Actually, the impact of the membrane upon the H2 O2 stress felt by the cell is greater when micromolar H2 O2 is present (9-fold less H2 O2 in the cell than out of the cell) than when millimolar H2 O2 is present (about 2-fold less H2 O2 in the cell than out of the cell). The ratio between maximal external H2 O2 and internal H2 O2 concentration also changes, reducing from 8 to 2 while external H2 O2 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 H2 O2 maximal concentration, which surprisingly does not depend on cell density. The external H2 O2 half-life and the cumulative internal H2 O2 exposure do depend upon cell density. Based on these analyses and in order to introduce a concept of dose response relationship for H2 O2-induced cell death, we developed the concepts of “maximal internal H2 O2 concentration” and “cumulative internal H2 O2 concentration” (e.g. the total amount of H2 O2). We predict that cumulative internal H2 O2 concentration is responsible for the H2 O2-mediated death of bacterial cells.

Highlights

Oxygen is indisputably essential for life, but it can impair cell ability to function normally or it can participate in its destruction ([1] and [2]) because of the generation of reactive oxygen species (ROS) like hydrogen peroxide (H2O2), superoxide (O2À) or hydroxyl radical (HO)
We investigated whether the decrease in E. coli survival with increasing exogenous H2O2 concentration was linked to theoretical maximum internal H2O2 concentration or to the rate of decrease in internal H2O2 concentration
An analysis of the most significant kinetic reactions confirmed that steady-state internal concentration H2O2 results from the balance between its production and a combination of Alkyl hydroperoxide reductase (Ahp) degradation (78%), Cat degradation (12%) and membrane permeability (10%)

Summary

Introduction

In order to better understand ROS dynamic within cells, we recently developed a mathematical model ([3]) for predicting reactive oxygen species (ROS) concentration and macromolecules oxidation invivo. This first study principally focuses on HO dynamic and its consequence on DNA whereas the current study will mainly focus on H2O2 dynamic. In order to build our mathematical model we used data from a large number of articles dealing with enzymes or molecule concentrations (in E. coli, kinetic properties and chemical reaction rate constants). We were able to propose a mathematical model based on a set of ordinary differential equations relating to fundamental principles of mass balance and reaction kinetics. It offers the possibility to simulate properly the experimental results obtained by biologists and to understand the biological parameters involved in the observed phenomena

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