Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes

Monther Abu-Remaileh, Gregory A. Wyant, Choah Kim, Nouf N. Laqtom, Maria Abbasi, Sze Ham Chan, Elizaveta Freinkman, David M. Sabatini

Research output: Contribution to journalArticlepeer-review

374 Scopus citations

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.
Original languageEnglish (US)
Pages (from-to)807-813
Number of pages7
JournalSCIENCE
Volume358
Issue number6364
DOIs
StatePublished - Nov 10 2017
Externally publishedYes

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Generated from Scopus record by KAUST IRTS on 2023-09-25

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