Increased Levels of Hydrogen Peroxide Induce a HIF-1-dependent Modification of Lipid Metabolism in AMPK Compromised C. elegans Dauer Larvae

SummaryCells have evolved numerous mechanisms to circumvent stresses caused by the environment, and many of them are regulated by the AMP-activated kinase (AMPK). Unlike most organisms, C. elegans AMPK-null mutants are viable, but they die prematurely in the “long-lived” dauer stage due to exhaustion of triglyceride stores. Using a genome-wide RNAi approach, we demonstrate that the disruption of genes that increase hydrogen peroxide levels enhance the survival of AMPK mutant dauers by altering both the abundance and the nature of the fatty-acid content in the animal by increasing the HIF-1-dependent expression of several key enzymes involved in fatty-acid biosynthesis. Our data provide a mechanistic foundation to explain how an optimal level of an often vilified ROS-generating compound such as hydrogen peroxide can provide cellular benefit, a phenomenon described as hormesis, by instructing cells to readjust their lipid biosynthetic capacity through downstream HIF-1 activation to correct cellular energy deficiencies.

► Increases in hydrogen peroxide levels stabilize HIF-1 protein
► Stabilized HIF-1 protein stimulated key enzymes involved in fatty-acid biosynthesis
► An optimal level of H2O2 was defined, which may correspond to a hormesis state
► Such a HIF-1-dependent metabolic adjustment may be critical for tumor growth