Abstract
SummaryAll organisms evolved defense mechanisms to counteract oxidative stress and buildup of reactive oxygen species (ROS). To test whether a potentially conserved mechanism exists for the rapid response, we investigated immediate metabolic dynamics of Escherichia coli, yeast, and human dermal fibroblasts to oxidative stress that we found to be conserved between species. To elucidate the regulatory mechanisms that implement this metabolic response, we developed mechanistic kinetic models for each organism's central metabolism and systematically tested activation and inactivation of each irreversible reaction by each metabolite. This ensemble modeling predicts in vivo relevant metabolite-enzyme interactions based on their ability to quantitatively describe metabolite dynamics. All three species appear to inhibit their oxidative pentose phosphate pathway during normal growth by the redox cofactor NADPH and relieve this inhibition to increase the pathway flux for detoxification of ROS during stress, with the sole exception of yeast when exposed to high levels of stress.
Highlights
The primeval accumulation of oxygen in the atmosphere was arguably one of the most dramatic changes for life on earth
Given previous knowledge on the dynamics of the oxidative stress responses (Ralser et al, 2009) (Kuehne et al, 2015) (Christodoulou et al, 2018), dynamic metabolome profiles were determined in triplicate experiments during 1 min for E. coli and S. cerevisiae and 5 min for human dermal fibroblast post stress
The ratio of oxidized to reduced glutathione increased after only 5 s and stabilized after about 10 s (HDF: 60 s), most pronounced upon treatment with 20 mM H2O2 (Figure S2A)
Summary
The primeval accumulation of oxygen in the atmosphere was arguably one of the most dramatic changes for life on earth It enabled higher respiratory energy yields due to the high redox potential of oxygen (Raymond and Segre , 2006), its reactive nature challenges all organisms through reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), that occur as by-products of aerobic respiration. Long-term transcriptional responses that scavenge ROS appear to be conserved across species (Ralser et al, 2007; Ray et al, 2012; Vatansever et al, 2013; Dan Dunn et al, 2015). Mammalian cells employ long-term anti-oxidative responses that entail ROS detoxification (Morgan and Liu, 2011; Gorrini et al, 2013; Ma, 2013) and, depending on the severity of stress, initiate either pro-survival gene expression programs that support NADPH production, ROS clearance, and DNA repair or cell death programs (Martindale and Holbrook, 2002; Morgan and Liu, 2011; Gorrini et al, 2013; Zhang et al, 2016)
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