The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans.
A mutation in a subunit of complex I of the mitochondrial electron transport chain (gas-1) causes Caenorhabditis elegans to be hypersensitive to volatile anesthetics and oxygen as well as shortening lifespan. We hypothesized that changes in mitochondrial respiration or reactive oxygen species production cause these changes. Therefore, we compared gas-1 to other mitochondrial mutants to identify the relative importance of these two aspects of mitochondrial function in determining longevity. Lifespans of gas-1 and mev-1 were decreased compared with N2, while that of clk-1 was increased. Rates of oxidative phosphorylation were decreased in all three mutants, but the ROS damage was decreased only in clk-1. Suppressors of gas-1 increased rates of oxidative phosphorylation, decreased oxidative damage to mitochondrial proteins and increased lifespan. Two strains containing combinations of mutations predicted to have very decreased complex I function, had unexpectedly long lifespans. We conclude that mitochondrial changes in lifespan appear to be mediated primarily by changes in oxidative damage rather than by changes in rates of oxidative phosphorylation. In contrast, the effects of mitochondrial changes on anesthetic sensitivity appear to be mediated by both altered respiration and oxidative damage.
Kayser
Ernst-Bernhard
EB
Department of Anesthesiology, University Hospitals and Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5007, USA.
Sedensky
Margaret M
MM
Morgan
Phil G
PG
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008136:Longevity / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000633:toxicity; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D016019:Survival Analysis
D018685:Anesthetics, Inhalation; C104339:CLK-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C468009:GAS-1 protein, C elegans; D010100:Oxygen