Cell Biology Peroxide Promotes Survival

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

Food deprivation causes Caenorhabditis elegans larvae to enter the developmentally arrested state of dauer. This process requires adenosine monophosphate–activated protein kinase (AMPK), which phosphorylates and inhibits ATGL1 (adipose triglyceride lipase 1) to prevent mobilization of triglyceride stores. C. elegans dauer larvae that lack AMPK die prematurely because of exhaustion of triglyceride stores. Xie and Roy performed an RNA interference (RNAi) screen and found that the survival of AMPK-null C. elegans dauer larvae was increased by loss of either ctl-1 or ctl-2, which encode catalase, an enzyme that catalyzes the decomposition of hydrogen peroxide (H₂O₂). The concentration of H₂O₂ was higher in AMPK- and catalase-null dauers than in AMPK-null dauers. Survival of catalase- and AMPK-null dauers was reduced by treatment with the antioxidant N-acetylcysteine, and survival of AMPK-null dauers was increased by treatment with H₂O₂. In AMPK- and catalase-null dauers, the increase in the concentration of H₂O₂ was attenuated by a loss-of-function mutation in daf-22, which encodes the terminal enzyme in peroxisomal fatty acid β-oxidation, which suggests that this process was the major source of H₂O₂ in AMPK- and catalase-null dauers. Reactive oxygen species, including H₂O₂, increase the transcriptional activity of hypoxia-inducible factor 1 (HIF-1), and AMPK- and catalase-null dauers showed increased activity of a reporter gene for HIF-1. Expression of genes encoding enzymes involved in fatty acid synthesis was increased in AMPK- and catalase-null dauers, and RNAi directed against HIF-1 reduced this increase in gene expression and also decreased survival. These results indicate that, in C. elegans, H₂O₂ produced by peroxisomal fatty acid β-oxidation can stimulate HIF-1 to increase lipid biosynthesis.

M. Xie, R. Roy, Increased levels of hydrogen peroxide induce a HIF-1-dependent modification of lipid metabolism in AMPK compromised C. elegans dauer larvae. Cell Metab. 16, 322–335 (2012). [PubMed]

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