Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion
By Mario Mauthe, I. Orhon, C. Rocchi, Xingdong Zhou, Morten Luhr, Kerst-Jan Hijlkema, R. Coppes, N. Engedal, M. Mari, F. Reggiori. Autophagy, 2018
1,861 citations recorded by the source corpus.
ABSTRACT 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.
Subfields: Epidemiology, Physiology
View Paper: https://www.semanticscholar.org/paper/284290d3918041fd3082cf7656f299e6197ec8c1
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Citations in the corpus
- Targeted protein degradation: mechanisms, strategies and application (2022, background): “The autophagosome then fuses with lysosomes to break down the contents.(27,28) Targeted protein degradation (TPD), via the proteasomal and lysosomal pathways, represent a novel tool to explore cellular pathways and a promising therapeutic approach.”
- Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro (2020, background): “Both CQ and HCQ are weak bases that are known to elevate the pH of acidic intracellular organelles, such as endosomes/lysosomes, essential for membrane fusion 5 .”