Previous work in C. elegans has shown that decreasing mitochondrial respiration can increase longevity. Several models have been proposed to account for this life span extension, including: (1) activation of the hypoxic response transcription factor, HIF-1, (2) reduced damage due to reactive oxygen species, (3) activation of a mitochondrial protein quality control pathway, and (4) an altered metabolic state permissive for longevity.  We have observed that RNAi knock-down of a subset of electron transport chain components can reduce polyglutamine toxicity. The goal of this project is to directly test whether the increase in lifespan and reduction in polyglutamine toxicity associated with impaired mitochondrial function is primarily due to the activation of HIF-1. We are testing this genetically using worms that either lack HIF-1 or over-express HIF-1 through deletion of vhl-1, a gene which targets HIF-1 for degradation. We are combining these mutants with RNAi knock-downs of various mitochondrial proteins and measuring lifespan and resistance to polyglutamine toxicity. 

People: Melana Yanos, Scott Leiser, Annie Chou, Marissa Fletcher, Melissa Primitivo