Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress.
BACKGROUND
Eukaryotic 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.


RESULTS
We 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.


CONCLUSIONS
The 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.
D000375:Aging / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D050260:Carbohydrate Metabolism / Q000187:drug effects; D003198:Computer Simulation; D004351:Drug Resistance; D055785:Gene Knockdown Techniques; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007716:Kluyveromyces / Q000201:enzymology / Q000235:genetics; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014305:Triose-Phosphate Isomerase / Q000235:genetics / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D016877:Oxidants; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D013481:Superoxides; D009249:NADP; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D014305:Triose-Phosphate Isomerase