The role of mitochondria-lysosome crosstalk in health and aging

项目摘要/摘要 长期以来，人们一直认为衰老导致的健康衰退与线粒体和溶酶体功能失调有关，但 这两个细胞器的故障是否有关联尚不清楚。此应用程序的总体目标是 描绘线粒体和溶酶体如何相互沟通以促进衰老时的健康。中环 假设线粒体和溶酶体通常相互沟通以促进健康，但 这在衰老过程中会受到影响，导致这两个细胞器共同退化为功能障碍。这是 初步数据显示，有缺陷的溶酶体可以激活线粒体应激途径 年轻的成年线虫。其基本原理是，在许多像帕金森氏症这样的衰老情况下，两者都 线粒体和溶酶体有缺陷或有家族性突变。如果线粒体之间的通讯 而溶酶体是很重要的，随着年龄的增长，健康状况的下降可能不仅是由于个体功能的丧失 细胞器也因失去了它们的协同交流而受到影响。因此，迫切需要了解 线粒体-溶酶体通讯如何适应衰老中的应激和细胞器功能障碍。中环 这一建议的假设将通过以下具体目标进行检验：1)确定应激信号通路 连接有缺陷的溶酶体和线粒体，2)确定在溶酶体到线粒体中的组织特异性作用。 衰老模型生物线虫中的线粒体信号，3)决定溶酶体到线粒体的方式 在衰老和帕金森氏症过程中信号的变化，以及增强这种信号是否可以拯救健康。 这一建议的应用是创新的，因为1)它关注线粒体的细胞器间反应 和溶酶体对衰老相关的应激反应，以及2)它将描绘线粒体-溶酶体在衰老相关应激中的通讯 多组织衰老生物秀丽线虫。先前在线粒体-溶酶体相互作用方面的工作使用单细胞 酵母和细胞培养等系统不能完全模拟衰老。本文提出的研究具有重要意义。 因为通过定义细胞所需的线粒体和溶酶体之间的一条新的通讯途径 应激和衰老的动态平衡，这一建议将为治疗开发提供策略，以恢复他们的 衰老过程中的交流。 除了实验研究，这份申请还提出了职业发展计划。沈医生的 职业目标是成为一名独立的、研究老龄化科学的学术研究员。完成此建议书将 允许她在衰老和增重过程中线粒体-溶酶体应激通讯方面建立一个研究利基 技术和领导技能是她发展成为一名独立调查员所必需的。帮助 为了实现她的目标，沈博士成立了一个科学咨询委员会来加深她的理解 溶酶体生物学、rna-seq和代谢组学。这一奖项也将给她一个提高自己的机会 科学写作、指导和沟通技能，以支持她转变为一名独立的调查人员。

PROJECT SUMMARY/ABSTRACT The decline of health in aging has long been associated with dysfunctional mitochondria and lysosomes, but whether the failure of these two organelles is linked remains unclear. The overall goal of this application is to delineate how mitochondria and lysosomes communicate with each other to promote health in aging. The central hypothesis is that mitochondria and lysosomes normally communicate with each other to promote health, but this becomes compromised during aging, leading the two organelles to co-devolve into dysfunction. This is supported by preliminary data showing that defective lysosomes can activate a mitochondrial stress pathway in young adult C. elegans. The rationale is that in many aging conditions like Parkinson's disease, both mitochondria and lysosomes are defective or have familial mutations. If communication between mitochondria and lysosomes is important, the health decline with aging may result from not only loss of function in the individual organelles but also from the loss of their synergistic communication. Thus, there is a critical need to understand how mitochondrial-lysosomal communication adapts to stress and organellar dysfunction in aging. The central hypothesis of this proposal will be tested by the following specific aims: 1) Identify the stress signaling pathway connecting defective lysosomes and mitochondria, 2) Define the tissue-specific roles in lysosome-to- mitochondrial signaling in the aging model organism C. elegans, 3) Determine how lysosome-to-mitochondrial signaling changes during aging and Parkinson's disease and whether boosting this signaling can rescue health. This proposed application is innovative because 1) it focuses on the inter-organellar response of mitochondria and lysosomes to aging-related stress and 2) it will delineate mitochondrial-lysosomal communication in the multi-tissue aging organism C. elegans. Previous work in mitochondrial-lysosomal interactions used single-celled systems like yeast and cell culture which cannot fully model aging. The research proposed here is significant because by defining a novel route of communication between mitochondria and lysosomes required for cellular homeostasis in stress and aging, this proposal will provide strategies for therapeutic development to restore their communication during aging. In addition to the experimental research, this application also proposes a career development plan. Dr. Shen's career goal is to become an independent, academic investigator in aging science. Completing this proposal will allow her to establish a research niche in mitochondrial-lysosomal stress communication in aging and gain technical and leadership skills that are essential for her development into an independent investigator. To help her achieve her goals, Dr. Shen has assembled a Scientific Advisory Committee to deepen her understanding of lysosomal biology, RNA-seq, and metabolomics. This award will also give her the opportunity to improve her scientific writing, mentorship, and communication skills to support her transition into an independent investigator.