Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

线粒体功能障碍是几乎所有年龄起病的神经退行性疾病的主要后果。 然而，在真核生物物种中，轻微的线粒体应激可以对人的寿命产生有益的影响 有机体。对线粒体在衰老过程中的作用的研究表明， 线虫在发育的关键窗口中的线粒体功能足以 延长生物体的寿命。在这段时间内，线粒体应激导致大量和持续的 通过对长寿命线粒体突变的分析证明基因表达模式的重组 动物。这种对早期新陈代谢应激的持续反应可能会使有机体适应其成体 新陈代谢以匹配预测的养分可利用性状态。 在此之前，我们曾报道过神经元线粒体功能的降低足以延长 线虫的寿命。轻微的神经元线粒体应激也导致脑内神经元表达上调。 线粒体应激信号横跨生物体的远端组织。我们现在报告的证据是 一类代谢神经递质在感知到的线粒体应激传播中的需求。 我们还观察到神经元特异性的表观遗传学重塑对线粒体功能障碍的反应。我们 假设在感觉到代谢应激后，神经元转录重塑其基因表达 通过激活一类神经元特异的染色质修饰酶来形成模式。基因转录的变化 然后神经元启动下游的神经内分泌信号事件，能够激活线粒体 跨越组织和器官的应激反应途径。这一连串的回应共同起到了 增加机体的新陈代谢能力和寿命。

Mitochondrial dysfunction is a primary consequence of nearly all age-onset neurodegenerative diseases. Across eukaryotic species, however, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Studies on the roles of mitochondria in the aging process have suggested that reduced mitochondrial function during a critical window of development in the nematode C. elegans is sufficient to extend the lifespan of the organism. Mitochondrial stress during this time results in a massive and persistent restructuring in gene expression patterns, as evidenced by analyses of long-lived mitochondrial mutant animals. This sustained response to an early metabolic stress may allow the organism to adapt its adult metabolism to match predicted states of nutrient availability. Previously, we reported that reduced mitochondrial function specifically in the neurons was sufficient to extend the lifespan of the nematode C. elegans. Mild neuronal mitochondrial stress also caused an upregulation in mitochondrial stress signaling across distal tissues of the organism. We now report evidence for the requirement of a class of metabolic neurotransmitters in the dissemination of perceived mitochondrial stress. We also observe a neuron-specific epigenetic remodeling in response to mitochondrial dysfunction. We hypothesize that, after sensing metabolic stress, neurons transcriptionally remodel their gene expression patterns by activating a class of neuron-specific chromatin modifying enzymes. Transcriptional changes in the neurons then initiate a downstream neuroendocrine signaling event that is capable of activating mitochondrial stress responsive pathways across tissues and organs. This cascade of responses collectively serves to increase the metabolic fitness and lifespan of the organism.