Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion
Open accessAbstract
Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradation. Autophagy is involved in the pathophysiology of numerous diseases and its modulation is beneficial for the outcome of numerous specific diseases. Several lysosomal inhibitors such as bafilomycin A1 (BafA1), protease inhibitors and chloroquine (CQ), have been used interchangeably to block autophagy in in vitro experiments assuming that they all primarily block lysosomal degradation. Among them, only CQ and its derivate hydroxychloroquine (HCQ) are FDA-approved drugs and are thus currently the principal compounds used in clinical trials aimed to treat tumors through autophagy inhibition. However, the precise mechanism of how CQ blocks autophagy remains to be firmly demonstrated. In this study, we focus on how CQ inhibits autophagy and directly compare its effects to those of BafA1. We show that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle. Furthermore, CQ induces an autophagy-independent severe disorganization of the Golgi and endo-lysosomal systems, which might contribute to the fusion impairment. Strikingly, HCQ-treated mice also show a Golgi disorganization in kidney and intestinal tissues. Altogether, our data reveal that CQ and HCQ are not bona fide surrogates for other types of late stage lysosomal inhibitors for in vivo experiments. Moreover, the multiple cellular alterations caused by CQ and HCQ call for caution when interpreting results obtained by blocking autophagy with this drug.
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CQ can also inflict severe disorganization of the Golgi and endo-lysosomal systems.
“Although CQ is primarily acknowledged as blocker of lysosomal degradation, a recent study by Mauthe et al.47 demonstrated that CQ can also inflict severe disorganization of the Golgi and endo-lysosomal systems.”
From AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields) (2018) · cites this paper as [47]
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- Authors
- Mauthe, M., Orhon, I., Rocchi, C., Zhou, X., Luhr, M., Hijlkema, K.-J., Coppes, R. P., Engedal, N., Mari, M., & Reggiori, F.
- Affiliations
- University Medical Center Groningen (NL)
- University of Oslo (NO)
- Corresponding author
- Mari, Muriel
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2018-07-20
- Volume
- 14
- Issue
- 8
- Pages
- 1435-1455
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC6103682
- OpenAlex
- W2810037075
- Cited by
- 2,122
- References
- 97
- Citations by year
- 2026: 230 · 2025: 292 · 2024: 277 · 2023: 267 · 2022: 300 · 2021: 332 · 2020: 311 · 2019: 102 · 2018: 8 · 2013: 1
- FWCI
- 147.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Autophagy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Figshare (cc-by)
- Funders
- H2020 Marie Skłodowska-Curie Actions (713660)
- KWF Kankerbestrijding (RUG2013-5792)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (DN82-303)
- Norges Forskningsråd (230686/F20)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII3_154421)
- ZonMw (016.130.606)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- chloroquine, hydroxychloroquine, autophagy inhibition, autophagosome-lysosome fusion, autophagic flux, lysosomal inhibitors, bafilomycin A1, endolysosomal system, lysosomal pH
- MeSH terms
- Autophagosomes, Sequestosome-1 Protein, Animals, Autophagy, Chloroquine, Endocytosis, Female, Golgi Apparatus, Humans, Hydroxychloroquine, Lysosomes, Membrane Fusion, Mice, Inbred C57BL, Endosomes, Macrolides, Cell Line, Tumor, Proteolysis, ErbB Receptors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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