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Hydrogen peroxide induced cell death: One or two modes of action?

ABSTRACT: Imlay and Linn show that exposure of logarithmically growing Escherichia coli to hydrogen peroxide (H2O2) leads to two kinetically distinguishable modes of cell killing. Mode one killing is pronounced near 1 mM concentration of H2O2 and is caused by DNA damage, whereas mode-two killing requires higher concentration ([Formula: see text]). The second mode seems to be essentially due to damage to all macromolecules. This phenomenon has also been observed in Fenton in vitro systems with DNA nicking caused by hydroxyl radical ([Formula: see text]). To our knowledge, there is currently no mathematical model for predicting mode one killing in vitro or in vivo after H2O2 exposure. We propose a simple model, using Escherichia coli as a model organism and a set of ordinary differential equations. Using this model, we show that available iron and cell density, two factors potentially involved in ROS dynamics, play a major role in the prediction of the experimental results obtained by our team and in previous studies. Indeed the presence of the mode one killing is strongly related to those two parameters. To our knowledge, mode-one death has not previously been explained. Imlay and Linn (Imlay and Linn, 1986) suggested that perhaps the amount of the toxic species was reduced at high concentrations of H2O2 because hydroxyl (or other) radicals might be quenched directly by hydrogen peroxide with the concomitant formation of superoxide anion (a less toxic species). We demonstrate (mathematically and numerically) that free available iron decrease is necessary to explain mode one killing which cannot appear without it and that H2O2 quenching or consumption is not responsible for mode-one death. We are able to follow ROS concentration (particularly responsible for mode one killing) after exposure to H2O2. This model therefore allows us to understand two major parameters involved in the presence or not of the first killing mode.

SUBMITTER: Uhl L

PROVIDER: S-EPMC4945851 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Hydrogen peroxide induced cell death: One or two modes of action?

Uhl Lionel L Gerstel Audrey A Chabalier Maialène M Dukan Sam S

Heliyon 20151223 4

Imlay and Linn show that exposure of logarithmically growing Escherichia coli to hydrogen peroxide (H2O2) leads to two kinetically distinguishable modes of cell killing. Mode one killing is pronounced near 1 mM concentration of H2O2 and is caused by DNA damage, whereas mode-two killing requires higher concentration ([Formula: see text]). The second mode seems to be essentially due to damage to all macromolecules. This phenomenon has also been observed in Fenton in vitro systems with DNA nicking ...[more]

PMID: 27441232

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Project description:Regulated cell death (RCD) encompasses the activation of cellular pathways that initiate and execute a self-dismissal process. RCD occur over a range of stressors doses that overcome pro-survival cellular pathways, while higher doses cause excessive damage leading to passive accidental cell death (ACD). Hydrogen peroxide (HP) has been proposed as a potential tool to control harmful cyanobacterial blooms, given its capacity to remove cyanobacterial cells and oxidize cyanotoxins. HP is a source of hydroxyl radicals and is expected to induce RCD only within a limited range of concentrations. This property makes this compound very useful to better understand stress-driven RCD. In this work, we analyzed cell death in microcystin-producing Microcystis aeruginosa by means of a stochastic dose response model using a wide range of HP concentrations (0, 0.29, 1.76, 3.67, 7.35, 14.70, and 29.5 mM). We used flow cytometry and unsupervised classification to study cell viability and characterize transitional cell death phenotypes after exposing cells to HP for 48 and 72 h. Non-linear regression was used to fit experimental data to a logistic cumulative distribution function (cdf) and calculate the half maximal effective concentration (EC50). The EC50 of M. aeruginosa exposed to HP were 3.77 ± 0.26 mM and 4.26 ± 0.22 mM at 48 and 72 h, respectively. The derivative of cdf (probability density function; pdf) provided theoretical and practical demonstration that EC50 is the minimal dose required to cause RCD in 50% of cells, therefore maximizing the probability of RCD occurrence. 1.76 mM HP lead to an antioxidant stress response characterized by increased reactive oxygen species (ROS) levels and HP decomposition activity. The exposure of 3.67 mM HP induced a dose-related transition in cell death phenotype, and produced several morphological changes (a less dense stroma, distortion of the cell membrane, partial disintegration of thylakoids, extensive cytoplasmic vacuolation and highly condensed chromatin). The EC50 and the stochastic cdf and pdf together with the multidimensional transitional phenotypic analysis of single cells contribute to further characterize cell death pathways in cyanobacteria.

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Hydrogen peroxide induced cell death: One or two modes of action?

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Hydrogen peroxide induced cell death: One or two modes of action?

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