Lysosomal Metabolomics and pH

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Abstract Lysosomes are highly specialized and dynamic cellular organelles, which constitute an acidic environment in the cell and are metabolic active by receiving and degrading macromolecules from the secretory, endocytic, autophagic and phagocytic trafficking pathways. At the same time, lysosomes act as the signaling center of the cell, and the metabolic status of the lysosome actively regulates nuclear transcription to govern various cellular activities, such as cell growth, metabolism and quality control. Misregulation of lysosomal activity has been associated with aging and age-associated diseases, including Alzheimer’s disease (AD). The Lysosomal Metabolomics and pH Core (Core C) will support three Research Projects in this PPG proposal to assess changes in lysosomal pH and metabolic activity through harnessing the power of high-throughput, high accuracy Mass Spectrometry (MS)-based metabolomics and high-resolution fluorescence lifetime imaging microscopy (FLIM). We will 1) perform lysosome-specific metabolomic profiling in aging and tauopathy mouse models, 2) assess lysosomal pH changes using FLIM. In addition, Core C will carry both technological and conceptual innovations by developing new technological platforms and by creating the first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome for mouse cortex and hippocampus in collaboration with Core A and Core B. Together, these studies will advance our current knowledge regarding the association between lysosomal functions and aging and AD tauopathy and provide powerful techniques and valuable resources to the fields of lysosomal biology, aging biology, and AD pathology.