Mitochondrial dysfunction in Caenorhabditis elegans causes metabolic restructuring, but this is not linked to longevity.
Lifespan in Caenorhabditis elegans, Drosophila, and mice can be extended by a decrease in mitochondrial electron transport chain (ETC) function, but the mechanism behind this extension is unknown. In the present study, we combine detailed metabolic analysis with lifespan determination following suppression of individual genes encoding respiratory complexes I-IV. We report that reduced complexes I, III, and IV activity extend lifespan but that complex II disruption does not. However, disruption to all four complexes affected metabolism in a similar manner suggesting that metabolic effects induced by ETC disruption are separable from lifespan extension. We found that suppression of ETC components induces a starvation-like metabolic response via the nuclear hormone receptor NHR-49. This includes induction of genes for mitochondrial fatty-acid β-oxidation (acs-2), the glyoxylate cycle (gei-7), gluconeogensis (PEPCK), and glycolysis (gpd-3). Interestingly, a null mutation of nhr-49 attenuated induction of these metabolic pathways, but did not affect the lifespan extension associated with decreases in complexes I, III, and IV function. Together, our results suggest that restructuring of metabolism via NHR-49 in C. elegans with mitochondrial dysfunction does not cause lifespan extension.
Zuryn
Steven
S
School of Chemical and Molecular Biosciences, University of Queensland, St Lucia, Queensland 4072, Australia.
Kuang
Jujiao
J
Tuck
Andrew
A
Ebert
Paul R
PR
D000255:Adenosine Triphosphate / Q000737:chemistry; D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000737:chemistry; D042967:Electron Transport Complex I / Q000235:genetics; D005786:Gene Expression Regulation; D008136:Longevity; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D034622:RNA Interference; D015854:Up-Regulation
D029742:Caenorhabditis elegans Proteins; D002241:Carbohydrates; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I