Disruption of mitochondrial dynamics affects behaviour and lifespan in Caenorhabditis elegans
Disruption of mitochondrial dynamics affects behaviour and lifespan in Caenorhabditis elegans
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DOI：
10.1007/s00018-019-03024-5
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发表时间：
2019-05-01
影响因子：
8
通讯作者：
Neumann, Brent
中科院分区：
文献类型：
--
作者：
Byrne, Joseph J.;Soh, Ming S.;Neumann, Brent
线粒体是真核细胞的重要组成部分，执行包括能量产生和钙缓冲在内的关键生理过程。因此，线粒体功能障碍与一系列人类疾病有关。它们功能的基础是通过裂变和聚变状态转变的能力，这是由几种 GTPases 调节的。在这里，我们开发了新的方法来非主观量化秀丽隐杆线虫肌肉和神经元细胞中的线粒体形态。使用这些技术，我们发现了当融合或裂变蛋白不存在时，线粒体形态中令人惊讶的组织特异性差异。通过超微结构分析，我们揭示了融合蛋白 FZO-1/mitofusin 2 在调节线粒体内膜结构中的新作用。此外，我们还确定了单个线粒体裂变（DRP-1/DRP1）和融合（FZO-1/mitofusin 1,2；EAT-3/OPA1）蛋白对动物行为和寿命的影响。我们发现，这些线粒体融合或裂变调节因子的丧失会导致动物运动以及肌肉和神经元功能出现年龄依赖性和进行性缺陷。我们的研究结果表明，在动物行为和组织功能方面，融合的破坏比缺乏裂变会导致更严重的缺陷，这意味着虽然整个生命都需要融合，但裂变在生命后期更为重要，可能会对抗与衰老相关的压力源。此外，我们的数据表明线粒体功能并不严格依赖于形态，形态变化和行为缺陷之间没有发现相关性。令人惊讶的是，我们发现线粒体裂变或融合的破坏显着降低了中位寿命，但最大寿命没有变化，这表明线粒体动力学在限制同基因群体寿命差异方面发挥着重要作用。总的来说，我们的研究为线粒体动力学在维持机体健康中的核心作用提供了重要的新见解。
Mitochondria are essential components of eukaryotic cells, carrying out critical physiological processes that include energy production and calcium buffering. Consequently, mitochondrial dysfunction is associated with a range of human diseases. Fundamental to their function is the ability to transition through fission and fusion states, which is regulated by several GTPases. Here, we have developed new methods for the non-subjective quantification of mitochondrial morphology in muscle and neuronal cells of Caenorhabditis elegans. Using these techniques, we uncover surprising tissue-specific differences in mitochondrial morphology when fusion or fission proteins are absent. From ultrastructural analysis, we reveal a novel role for the fusion protein FZO-1/mitofusin 2 in regulating the structure of the inner mitochondrial membrane. Moreover, we have determined the influence of the individual mitochondrial fission (DRP-1/DRP1) and fusion (FZO-1/mitofusin 1,2; EAT-3/OPA1) proteins on animal behaviour and lifespan. We show that loss of these mitochondrial fusion or fission regulators induced age-dependent and progressive deficits in animal movement, as well as in muscle and neuronal function. Our results reveal that disruption of fusion induces more profound defects than lack of fission on animal behaviour and tissue function, and imply that while fusion is required throughout life, fission is more important later in life likely to combat ageing-associated stressors. Furthermore, our data demonstrate that mitochondrial function is not strictly dependent on morphology, with no correlation found between morphological changes and behavioural defects. Surprisingly, we find that disruption of either mitochondrial fission or fusion significantly reduces median lifespan, but maximal lifespan is unchanged, demonstrating that mitochondrial dynamics play an important role in limiting variance in longevity across isogenic populations. Overall, our study provides important new insights into the central role of mitochondrial dynamics in maintaining organismal health.