The Role of the Lysosome in Aging

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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.