Abstract
BackgroundEukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. Among these processes, metabolic alterations seem to play an important role.ResultsWe recently discovered that yeast cells with reduced activity of the key glycolytic enzyme triosephosphate isomerase exhibit an increased resistance to the thiol-oxidizing reagent diamide. Here we show that this phenotype is conserved in Caenorhabditis elegans and that the underlying mechanism is based on a redirection of the metabolic flux from glycolysis to the pentose phosphate pathway, altering the redox equilibrium of the cytoplasmic NADP(H) pool. Remarkably, another key glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is known to be inactivated in response to various oxidant treatments, and we show that this provokes a similar redirection of the metabolic flux.ConclusionThe naturally occurring inactivation of GAPDH functions as a metabolic switch for rerouting the carbohydrate flux to counteract oxidative stress. As a consequence, altering the homoeostasis of cytoplasmic metabolites is a fundamental mechanism for balancing the redox state of eukaryotic cells under stress conditions.
Highlights
Eukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress
As a consequence, altering the homoeostasis of cytoplasmic metabolites is a fundamental mechanism for balancing the redox state of eukaryotic cells under stress conditions
It is remarkable that the expression of a subset of glycolytic proteins and proteins implicated in related pathways is repressed, while the expression of a few enzymes involved in the pentose phosphate pathway (PPP), which is directly connected to the glycolytic pathway, is induced under oxidative stress conditions [1]
Summary
Eukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. We discovered that yeast cells with reduced catalytic activity of another key glycolytic enzyme, triosephosphate isomerase (TPI), are highly resistant to the oxidant diamide [11] This essential enzyme precedes GAPDH in glycolysis, catalyzing the interconversion of dihydroxyacetone phosphate (dhap) and gly3p, the substrate of GAPDH, and a reduction in its activity results in an elevated cellular dhap concentration [12,13,14]. By combining genetic and quantitative metabolite analyses along with in silico modeling, we present the first direct proof that eukaryotic cells actively reroute the metabolic flux from glycolysis to the PPP as an immediate and protective response to counteract oxidative stress
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