The dynamin-related protein DRP-1 and the insulin signaling pathway cooperate to modulate Caenorhabditis elegans longevity

Abstract

Here, we report that inactivation of the Caenorhabditis elegans dynamin-related protein DRP-1, a key component responsible for mitochondrial fission and conserved from yeast to humans, dramatically enhanced the effect of reduced insulin signaling (IIS) to extend lifespan. This represents the first report of a beneficial impact of manipulating mitochondrial dynamics on animal lifespan and suggests that mitochondrial morphology and IIS cooperate to modulate aging.

Figure 1. Loss of drp-1 enhances the longevity phenotype of IIS mutant worms in a daf-16-dependent manner

(A) Mean adult lifespan (⁺/- s.d) of wild-type, age-1 and daf-2 mutant worms treated with empty vector (empty bars) or drp-1 RNAi (red bars). Note that quantitative PCR data showed that drp-1 mRNA expression was reduced by ~50% in all strains upon drp-1 RNAi treatment (data not shown). Adult lifespan of wild-type and drp-1 mutant worms (B); age-1 and age-1;drp-1 mutant worms (C); daf-2 and daf-2;drp-1 mutant worms (D) treated or not with daf-16 RNAi (as indicated). Quantitative data and statistical analysis are presented in Table S1.

Figure 2. Loss of drp-1 affects mitochondrial morphology and stress resistance without affecting DAF-16 sub-cellular localization

(A) Percentage of worms alive (⁺/- s.d) after 8 hours at 37°C (upper graph) and mean survival (⁺/- s.d) upon treatment with 25 mM paraquat (bottom graph) in the indicated strains. * indicates p<0.001 (Student’s t-test for heat stress and log-rank test for paraquat). TMRE staining (B) and circularity index (⁺/- s.d) (C) of the mitochondrial network in the indicated strains. In (C), * indicates p<0.005 when compared to single mutant counterpart and p<0.005 when compared to wild-type worms using a Student’s t-test. In agreement with previous studies (Labrousse et al. 1999), drp-1 mutant worms exhibited disrupted structure of the tubular mitochondrial network in which mitochondria tended to form large blebs as reflected by an increased circularity index. (D) DAF-16∷GFP was categorized by sub-cellular localization in daf-2 worms treated with empty vector or drp-1 RNAi. The data obtained at Day 3 of adulthood are presented.