Interrogation of the cellular and subcellular architecture of nutrient metabolism in conditions of dietary restriction

项目摘要/摘要 将代谢资源重新分配到促进身体维持的细胞过程中是一个长期的过程。 持有假说，以解释不同的长寿范式如何促进更健康的衰老。最好的模型之一 这个假设是饮食限制(DR)，它在保持动物健康的同时优化新陈代谢效率 和长寿。然而，令人惊讶的是，我们几乎没有洞察到具体的营养资源是如何不同的 DR在细胞水平上的利用除了改变新陈代谢过程外，DR还促进了戏剧性的 细胞器结构和功能的重塑。我们越来越了解到，不仅是一个 对其功能状态至关重要的离散细胞器，以及所形成的空间关系和接触点 在不同的细胞器网络之间。因此，整个亚细胞结构的重组起着至关重要的作用 在决定代谢性能方面的作用。然而，我们的初步数据表明，与年龄相关的 分子损伤的积累导致内质网(ER)的重构，内质网是细胞间相互作用的枢纽 细胞器交流。因此，我们的主要假设是细胞器间相互作用的重塑是 既是衰老细胞丧失功能弹性的关键途径，也是DR介导的重要机制 新陈代谢的重新编程。为了推进这一假设，我们提出了利用新的关联电子 结合小鼠和线虫模型的显微镜(EM)和稳定同位素成像技术 为DR如何重组细胞器相互作用组和重新分配营养流量建立一个框架 细胞器。总之，这项提案旨在为DR如何重塑细胞器建立一个框架 促进健康老龄化的互动组，重点是ER的作用。

Project Summary/Abstract The re-allocation of metabolic resources towards cell processes that promote somatic maintenance is a long- held hypothesis to explain how diverse longevity paradigms promote healthier aging. One of the best models of this hypothesis is dietary restriction (DR), which optimizes metabolic efficiency while maintaining animal fitness and longevity. However, we possess surprisingly little insight into how specific nutrient resources are differentially utilized at the cell level during DR. In addition to altering metabolic processes, DR promotes a dramatic remodeling of organelle structures and functions. Increasingly we understand that not only is the structure of a discrete organelle critical for its functional state, but also the spatial relationships and contact sites formed between different organelle networks. The restructuring of the overall subcellular architecture thus plays a critical role in determining metabolic performance. However, our preliminary data suggest that age-dependent accumulation of molecular damage causes remodeling of the endoplasmic reticulum (ER), a hub of inter- organellar communication. Our overarching hypothesis is thus that remodeling of inter-organelle interactions is is both a key route by which aging cells lose functional resilience and an essential mechanism of DR-mediated reprogramming of metabolism. To advance this hypothesis we propose to exploit new correlative electron microscopy (EM) and stable isotope imaging technology in a combination of mouse and C. elegans models to establish a framework for how DR restructures the organelle interactome and re-allocates nutrient flux between organelles. Altogether this proposal aims to establish a framework for how DR remodels the organelle interactome to promote healthy aging with a focus on the role of the ER.