Traa Annika, Shields Hazel, AlOkda Abdelrahman, Rudich Zenith D, Ko Bokang, Van Raamsdonk Jeremy M
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Front Aging. 2023 May 16;4:1145198. doi: 10.3389/fragi.2023.1145198. eCollection 2023.
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 on lifespan and stress resistance in the long-lived mitochondrial mutants and in . Loss of markedly reduced the long lifespans of both mitochondrial mutants. Disruption of also decreased resistance to chronic oxidative stress in and mutants but had little or no detrimental effect on resistance to other stressors. In contrast, inhibition had no effect on oxidative stress resistance or lifespan in worms when DAF-16 is absent, suggesting that the effect of on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion of markedly decreases both phenotypes in worms, which could result in a floor effect. In exploring the contribution of DAF-16 further, we found that disruption of did not affect the nuclear localization of DAF-16 in worms or prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants. This suggests the possibility that the effect of 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.
导致线粒体功能轻度受损的突变可延长寿命。先前的研究表明，寿命的延长依赖于应激反应转录因子，包括DAF-16/FOXO，它在长寿线粒体突变体中核定位增加。我们最近发现，DAF-16在细胞内的定位依赖于内体运输蛋白TBC-2。基于DAF-16在寿命和抗应激方面的重要作用，我们研究了破坏TBC-2对长寿线粒体突变体线虫的寿命和抗应激能力的影响。TBC-2的缺失显著缩短了两种线粒体突变体的长寿命。破坏TBC-2也降低了线虫和突变体对慢性氧化应激的抵抗力，但对其他应激源的抵抗力几乎没有或没有不利影响。相比之下，当DAF-16缺失时，抑制TBC-2对蠕虫的氧化应激抵抗力或寿命没有影响，这表明TBC-2对线粒体突变体寿命的影响可能是由DAF-16的错误定位介导的。然而，这一结果因TBC-2的缺失显著降低了线虫的两种表型这一事实而变得复杂，这可能导致一种下限效应。在进一步探索DAF-16的作用时，我们发现破坏TBC-2并不影响线虫中DAF-16的核定位，也不会阻止长寿线粒体突变体中DAF-16靶基因的上调。这表明，TBC-2对长寿线粒体突变体的寿命和抗应激能力的影响至少部分独立于其对DAF-16定位的影响。总体而言，这项工作证明了内体运输对于线粒体功能轻度受损导致的寿命延长和抗应激能力增强的重要性。
