Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

摘要 线粒体缺陷被认为与许多疾病有关。由于线粒体的多样性 功能，许多蛋白质必须输入细胞器，适当折叠，并组装成大的 具有适当化学计量比的络合物。这些过程中的任何一个失败都是灾难性的，如展开、错误折叠、 甚至不适当数量的蛋白质可能会导致细胞器功能的丧失。因此，有几个 线粒体质量控制机制存在，确保细胞器内的动态平衡。很多--如果不是全部的话 -这些质量控制机器中已显示出在老化过程中功能下降，使 线粒体质量控制是我们理解衰老的一个有趣的方面. 在过去的十年里，我们利用遗传上易驯化的线虫线虫发现， 神经元线粒体功能障碍，能够在远端诱发UPRmt的远期效应 组织，这对生物生理学有直接的影响。此外，我们实验室的研究表明，诱导 仅在神经元中UPRmt JMJD-1.2/PHF8的正性调节因子的活性能够产生有益的 影响，包括延长寿命，这是由UPRmt的系统激活介导的。的能力 神经元传递应激并不是UPRmt所特有的，因为类似的发现已经在非 UPRER和胞质热休克反应(HSR)的自主通讯。此外，虽然神经元 一直处于神经生物学领域的科学研究中心，我们最近发现神经胶质细胞是一种 重要的细胞类型，介导细胞对生理应激反应和寿命的非自主激活。在……里面 具体地说，我们发现星形细胞样的CEPsh胶质细胞足以在整个 有机体，类似于神经元。因此，我们假设神经胶质细胞可能能够协调激活 组织之间的UPRmt通过一种与UPRER不同的机制进行。我们的主要假设是 星形胶质细胞可以在远端组织中启动UPRmt的激活，从而直接影响 身体健康。 在这个提案中，我们概述了我们的策略，以阐明神经胶质细胞和神经元之间的相互作用，以及它们之间的 生物体对寿命和抗应激能力的影响。了解此通信，无论是在 生理和分子水平，不仅将绘制出与长寿相关的调节和细胞变化， 但也将阐明神经胶质在神经系统中发挥的新功能，使我们更接近 了解神经系统及其在调节寿命方面的关键作用。

ABSTRACT Defects of the mitochondria have been implicated in many diseases. Due to the diverse set of mitochondrial functions, many proteins must be imported into the organelle, properly folded, and assembled into large complexes with proper stoichiometry. Failure in any of these processes is disastrous, as unfolding, misfolding, or even improper numbers of proteins may cause loss of function of the organelle. Accordingly, several mitochondrial quality control mechanisms exist, which ensure homeostasis within the organelle. Many – if not all – of these quality control machineries have been shown to functionally decline during the aging process, making mitochondrial quality control an intriguing aspect in our understanding of aging. Over the last decade, we have discovered, using the genetically-tractable nematode C. elegans, that mitochondrial dysfunction in neurons, is capable of eliciting long-range effects of inducing the UPRmt in distal tissues, which has direct implications on organismal physiology. Further, work by our lab showed that inducing the activity of the positive regulator of UPRmt JMJD-1.2/PHF8 solely in neurons is capable of eliciting beneficial effects, including prolonged lifespan, that is mediated by systemic activation of the UPRmt. The capacity of neurons to communicate stress is not specific to UPRmt, as similar findings have been reported in non- autonomous communication of UPRER and the cytosolic heat-shock response (HSR). Moreover, while neurons have been at the center of scientific research in the field of neurobiology, we have recently identified glia as an important cell type mediating cell non-autonomous activation of physiological stress responses and lifespan. In particular, we identified astrocyte-like CEPsh glia to be sufficient in communicating long-range UPRER across the organism, similar to neurons. Therefore, we hypothesize that glial cells may be able to coordinate the activation of the UPRmt between tissues through a mechanism distinct to that of the UPRER. Our main hypothesis is that astrocyte-like glia can initiate the activation of UPRmt in distal tissues, which can directly impact organismal health. In this proposal, we outline our strategy to elucidate the interaction between glia and neurons, and their organismal effects on longevity and stress resistance. Understanding this communication, both on the physiological and molecular level, will not only map the regulatory and cellular changes associated with longevity, but will also shed light on novel functions that glia serve in the nervous system, bringing us closer to understanding the nervous system, and its critical role in regulating lifespan.