Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes
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Author(s)
Chan, Sze Ham
Freinkman, Elizaveta
Abu-Remaileh, Monther
Wyant, Gregory Andrew
Kim, Choah
Laqtom, Nouf N
Abbasi, Maria
Sabatini, David
Date Issued
November 2017
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Abu-Remaileh, Monther et al. “Lysosomal Metabolomics Reveals V-ATPase- and mTOR-Dependent Regulation of Amino Acid Efflux from Lysosomes.” Science 358, 6364 (October 2017): 807–813 © 2017 American Association for the Advancement of Science
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Author's final manuscript
Abstract
The lysosome degrades and recycles macromolecules, signals to the cytosol and nucleus, and is implicated in many diseases. Here, we describe a method for the rapid isolation of mammalian lysosomes and use it to quantitatively profile lysosomal metabolites under various cell states. Under nutrient-replete conditions, many lysosomal amino acids are in rapid exchange with those in the cytosol. Loss of lysosomal acidification through inhibition of the vacuolar H+–adenosine triphosphatase (V-ATPase) increased the luminal concentrations of most metabolites but had no effect on those of the majority of essential amino acids. Instead, nutrient starvation regulates the lysosomal concentrations of these amino acids, an effect we traced to regulation of the mechanistic target of rapamycin (mTOR) pathway. Inhibition of mTOR strongly reduced the lysosomal efflux of most essential amino acids, converting the lysosome into a cellular depot for them. These results reveal the dynamic nature of lysosomal metabolites and that V-ATPase- and mTOR-dependent mechanisms exist for controlling lysosomal amino acid efflux.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1126/SCIENCE.AAN6298
