AUTHOR=Traa Annika , Shields Hazel , AlOkda Abdelrahman , Rudich Zenith D. , Ko Bokang , Van Raamsdonk Jeremy M. 

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

JOURNAL=Frontiers in Aging

VOLUME=4

YEAR=2023

URL=https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2023.1145198

DOI=10.3389/fragi.2023.1145198

ISSN=2673-6217

ABSTRACT=<p>Mutations 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 disrupting <italic>tbc-2</italic> on lifespan and stress resistance in the long-lived mitochondrial mutants <italic>nuo-6</italic> and <italic>isp-1</italic> in <italic>Caenorhabditis elegans</italic>. Loss of <italic>tbc-2</italic> markedly reduced the long lifespans of both mitochondrial mutants. Disruption of <italic>tbc-2</italic> also decreased resistance to chronic oxidative stress in <italic>nuo-6</italic> and <italic>isp-1</italic> mutants but had little or no detrimental effect on resistance to other stressors. In contrast, <italic>tbc-2</italic> inhibition had no effect on oxidative stress resistance or lifespan in <italic>isp-1</italic> worms when DAF-16 is absent, suggesting that the effect of <italic>tbc-2</italic> on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion of <italic>daf-16</italic> markedly decreases both phenotypes in <italic>isp-1</italic> worms, which could result in a floor effect. In exploring the contribution of DAF-16 further, we found that disruption of <italic>tbc-2</italic> did not affect the nuclear localization of DAF-16 in <italic>isp-1</italic> worms or prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants. This suggests the possibility that the effect of <italic>tbc-2</italic> on 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.</p>