Abstract
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.
Conclusion:
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / physiology
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Amino Acid Substitution
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Animals
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism*
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Carbohydrate Metabolism* / drug effects
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Computer Simulation
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Drug Resistance
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Gene Knockdown Techniques
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Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / genetics
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Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / physiology
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Glycolysis / drug effects
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Glycolysis / physiology
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Humans
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Kluyveromyces / enzymology
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Kluyveromyces / genetics
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Models, Biological
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NADP / metabolism
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Oxidants / pharmacology
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Oxidative Stress* / drug effects
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Oxidative Stress* / physiology
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Pentose Phosphate Pathway / drug effects
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / genetics
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Superoxides / metabolism
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Triose-Phosphate Isomerase / genetics
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Triose-Phosphate Isomerase / physiology*
Substances
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Caenorhabditis elegans Proteins
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Oxidants
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Recombinant Fusion Proteins
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Saccharomyces cerevisiae Proteins
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Superoxides
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NADP
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Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)
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Triose-Phosphate Isomerase