Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Abstract

AbstractMutations that result in a mild impairment of mitochondrial function can extend longevity. Previous studies have shown that the increase in lifespan is dependent on stress responsive transcription factors, including DAF-16/FOXO, which exhibits increased nuclear localization in long-lived mitochondrial mutants. We recently found that the localization of DAF-16 within the cell is dependent on the endosomal trafficking protein TBC-2. Based on the important role of DAF-16 in both longevity and resistance to stress, we examined the effect of disruptingtbc-2on lifespan and stress resistance in the long-lived mitochondrial mutantsnuo-6andisp-1inC. elegans. Loss oftbc-2markedly reduced the long lifespans of both mitochondrial mutants. Disruption oftbc-2also decreased resistance to specific exogenous stressors innuo-6andisp-1mutants. In contrast,tbc-2inhibition had no effect on oxidative stress resistance or lifespan inisp-1worms when DAF-16 is absent suggesting that the effect oftbc-2on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion ofdaf-16markedly decreases both phenotypes inisp-1worms. Surprisingly, disruption oftbc-2did not prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants, suggesting the possibility that the effect oftbc-2on lifespan and stress resistance in the long-lived mitochondrial mutants is at least partially independent of its effects on DAF-16 localization. Overall, this work demonstrates the importance of endosomal trafficking for the extended longevity and enhanced stress resistance resulting from mild impairment of mitochondrial function.