Abstract:
The 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, Drosophila and C. elegans. Disruption of the mitochondrial fission gene drp-1 drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with RNA interference clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels, food consumption or mitochondrial membrane potential. Disruption of mitophagy through RNA interference targeting pink-1 decreased the lifespan of daf-2;drp-1 worms suggesting that increased mitophagy contributes to their extended lifespan. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.
摘要:
线粒体网络的动态性质受线粒体裂变和融合调节,允许线粒体重新组织以适应细胞不断变化的需求。随着生物年龄的增长,线粒体裂变和融合变得失调,线粒体网络变得越来越支离破碎。线粒体动力学的调节已被证明会影响真菌的寿命,酵母,果蝇和秀丽隐杆线虫。线粒体裂变基因drp-1的破坏急剧增加了daf-2胰岛素/IGF-1信号(IIS)突变体的已经长的寿命。在这项工作中,我们确定了drp-1破坏以延长daf-2寿命所需的条件,并探索了相关的分子机制。我们发现在开发过程中击倒drp-1足以延长daf-2的寿命,而神经元中drp-1的组织特异性敲除,肠道或肌肉未能增加daf-2的寿命。与线粒体裂变有关的其他基因的破坏也增加了daf-2的寿命,就像用减少线粒体片段化的RNA干扰克隆处理一样。在探索潜在的机制时,我们发现drp-1的缺失增加了对慢性应激的抵抗力。此外,我们发现drp-1的破坏增加了daf-2蠕虫的线粒体和过氧化物酶体连接,增加氧化磷酸化和ATP水平,daf-2蠕虫的线粒体自噬增加,但不影响他们的ROS水平,食物消耗或线粒体膜电位。通过靶向pink-1的RNA干扰破坏线粒体自噬会降低daf-2的寿命;drp-1蠕虫表明线粒体自噬的增加有助于延长寿命。总的来说,这项工作定义了drp-1破坏增加daf-2寿命的条件,并确定了daf-2的多种变化;drp-1突变体可能有助于其寿命延长。