Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

线粒体功能障碍是几乎所有年龄发作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细胞的寿命产生有益的影响。 有机体对线粒体在衰老过程中作用的研究表明， 线粒体功能在线虫C.优雅足以 延长有机体的寿命。在此期间线粒体压力导致大规模和持续的 基因表达模式的重组，如长寿线粒体突变体的分析所证明的 动物这种对早期代谢应激的持续反应可能使生物体能够适应其成年 代谢，以配合预测的状态养分的可用性。 以前，我们报道过，减少线粒体功能，特别是在神经元中，足以延长 线虫C.优雅轻度的神经元线粒体应激也引起了 线粒体应激信号在生物体的远端组织中传递。我们现在报告的证据 在线粒体应激的传播中需要一类代谢性神经递质。 我们还观察到一个神经元特异性的表观遗传重塑线粒体功能障碍。我们 假设在感受到代谢应激后，神经元转录重塑其基因表达 通过激活一类神经元特异性染色质修饰酶来改变模式。转录变化 然后神经元启动下游神经内分泌信号传导事件， 组织和器官的应激反应途径。这一连串的反应共同作用于 增加机体的代谢适应性和寿命。

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.