{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:55:56Z","timestamp":1793134556159,"version":"4.5.0"},"reference-count":58,"publisher":"Portland Press Ltd.","issue":"4","license":[{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Autophagy is dependent upon lysosomes, which fuse with the autophagosome to complete the autophagic process and whose acidic interior permits the activity of their intraluminal degradative enzymes. Chloroquine (CQ) and bafilomycin A1 (BafA) each cause alkalinisation of the lumen and thus impair lysosomal function, although by distinct mechanisms. CQ diffuses into lysosomes and undergoes protonation, while BafA inhibits the ability of the vacuolar type H+-ATPase (v-ATPase) to transfer protons into the lysosome. In the present study, we examine the impact of CQ and BafA on the activity of mammalian target of rapamycin complex 1 (mTORC1), inhibition of which is an early step in promoting autophagy. We find each compound inhibits mTORC1 signalling, without affecting levels of protein components of the mTORC1 signalling pathway. Furthermore, these effects are not related to these agents\u2019 capacity to inhibit autophagy or the reduction in amino acid supply from lysosomal proteolysis. Instead, our data indicate that the reduction in mTORC1 signalling appears to be due to the accumulation of lysosomal storage material. However, there are differences in responses to these agents, for instance, in their abilities to up-regulate direct targets of transcription factor EB (TFEB), a substrate of mTORC1 that drives transcription of many lysosomal and autophagy-related genes. Nonetheless, our data imply that widely used agents that alkalinise intralysosomal pH are mimetics of acute lysosomal storage disorders (LSDs) and emphasise the importance of considering the result of CQ and BafA on mTORC1 signalling when interpreting the effects of these agents on cellular physiology.<\/jats:p>","DOI":"10.1042\/bsr20200905","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T07:04:10Z","timestamp":1586847850000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling"],"prefix":"10.1042","volume":"40","author":[{"given":"Anthony\u00a0O.","family":"Fedele","sequence":"first","affiliation":[{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide 5001, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0704-6442","authenticated-orcid":false,"given":"Christopher\u00a0G.","family":"Proud","sequence":"additional","affiliation":[{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide 5001, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"2021111620083042500_B1","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR signaling in growth, metabolism, and disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"2021111620083042500_B2","doi-asserted-by":"publisher","first-page":"5386","DOI":"10.1074\/jbc.R117.810366","article-title":"A molecular perspective of mammalian autophagosome biogenesis","volume":"293","author":"Mercer","year":"2018","journal-title":"J. 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