Developmental disruption of the mitochondrial fission genedrp-1extends the longevity ofdaf-2insulin/IGF-1 receptor mutant

Abstract

AbstractThe dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell’s ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast,DrosophilaandC. elegans. While disruption of the mitochondrial fission genedrp-1only mildly increases wild-type lifespan, it drastically increases the already long lifespan ofdaf-2insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required fordrp-1disruption to extenddaf-2longevity and explored the molecular mechanisms involved. We found that knockdown ofdrp-1during development is sufficient to extenddaf-2lifespan, while tissue-specific knockdown ofdrp-1in neurons, intestine or muscle failed to increasedaf-2longevity. Disruption of other genes involved in mitochondrial fission also increaseddaf-2lifespan as did treatment with a number of different RNAi clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion ofdrp-1increases resistance to chronic stresses and slows physiologic rates indaf-2worms. In addition, we found that disruption ofdrp-1increased mitochondrial and peroxisomal connectedness indaf-2worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy indaf-2worms, but did not affect their ROS levels or mitochondrial membrane potential. Overall, this work defined the conditions under whichdrp-1disruption increasesdaf-2lifespan and has identified multiple changes indaf-2;drp-1mutants that may contribute to their lifespan extension.