The Role of the Lysosome in Aging

项目摘要/摘要 溶酶体是酸性细胞器，在蛋白质周转、营养信号和代谢物中起主要作用。 储藏室。氨基酸和离子在溶酶体中被分隔开来，营养信号通路很重要 对于寿命调节，如雷帕霉素(TOR)途径的靶点，在溶酶体上感觉营养物质 浮出水面。溶酶体功能受损长期以来被认为与许多 与年龄相关的疾病。然而，溶酶体功能障碍如何导致机体衰老仍不清楚。 我们实验室最近的工作已经开始阐明这个问题。使用酵母作为模型系统，我们展示了 溶酶体失效是衰老过程中细胞衰退的主要驱动因素，它的崩溃导致 严重的线粒体功能障碍。令人惊讶的是，与之前大多数研究不同的是， 溶酶体损伤引起的线粒体衰退是由于溶酶体蛋白分解减少所致。 发现线粒体功能障碍并不是由于溶酶体崩溃时蛋白质降解的损失造成的， 相反，这是因为有缺陷的溶酶体无法有效地隔离和分隔氨基酸。 基于这些结果，我们认为溶酶体中氨基酸空间区划的失败 干扰线粒体功能，是衰老和溶酶体相关的重要驱动因素 精神错乱。这一提议的中心目标是通过以下方式来检验这一假说：1)确定线粒体缺陷 溶酶体受损的细胞；2)确定溶酶体的什么功能对调节 线粒体功能；3)阐明溶酶体-线粒体连接在衰老和衰老中的作用 哺乳动物系统；以及4)定义保护细胞免受溶酶体功能障碍的新途径。总而言之， 我们的研究结果将提供对溶酶体功能方面的洞察，这些方面对其在 延年益寿，预防疾病。

PROJECT SUMMARY/ABSTRACT Lysosomes are acidic organelles that play major roles in protein turnover, nutrient signaling, and metabolite storage. Amino acids and ions are compartmentalized in lysosomes, and nutrient-signaling pathways important for lifespan regulation such as the Target of Rapamycin (TOR) pathway sense nutrients at the lysosomal surface. Impaired lysosomal function has long been linked to the aging process and development of numerous age-associated diseases. However, how lysosomal dysfunction contributes to organismal aging is still unclear. Recent work from our lab has begun to shed light on this question. Using yeast as a model system, we showed that lysosome failure is a major driver of cellular decline during the aging process, and its collapse leads to profound mitochondrial dysfunction. Surprisingly, unlike the majority of previous studies that have suggested that mitochondrial decline caused by lysosome impairment results from decreased lysosomal proteolysis, we found that mitochondrial dysfunction does not result from loss of protein degradation upon lysosome collapse, but instead, from the inability of faulty lysosomes to effectively sequester and compartmentalize amino acids. Based on these results, we propose that failure to spatially compartmentalize amino acids in lysosomes interferes with mitochondrial function, and serves as an important driver of aging and lysosome-related disorders. The central goal of this proposal is to test this hypothesis by: 1) identifying mitochondrial deficits in lysosome-impaired cells; 2) determining what function of the lysosome is important for regulation of mitochondrial function; 3) elucidating the role of the lysosome-mitochondria connection in aging and mammalian systems; and 4) defining new pathways that protect cells from lysosome dysfunction. Collectively, the results of our studies will provide insight into the aspects of lysosome function important for its role in lifespan preservation and disease prevention.