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Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine
Abstract
Hydroxychloroquine (HCQ) is a lysosomotropic amine with cytotoxic properties. Here, we show that HCQ induces signs of lysosomal membrane permeabilization (LMP), such as the decrease in the lysosomal pH gradient and the release of cathepsin B from the lysosomal lumen, followed by signs of apoptosis including caspase activation, phosphatidylserine exposure, and chromatin condensation with DNA loss. HCQ also induces mitochondrial membrane permeabilization (MMP), as indicated by the insertion of Bax into mitochondrial membranes, the conformational activation of Bax within mitochondria, the release of cytochrome c from mitochondria, and the loss of the mitochondrial transmembrane potential. To determine the molecular order among these events, we introduced inhibitors of LMP (bafilomycin A(1)), MMP (Bcl-X(L), wild-type Bcl-2, mitochondrion-targeted Bcl-2, or viral mitochondrial inhibitor of apoptosis from cytomegalovirus), and caspases (Z-VAD.fmk) into the system. Our data indicate that caspase-independent MMP is rate-limiting for LMP-mediated caspase activation. Mouse embryonic fibroblasts lacking the expression of both Bax and Bak are resistant against hydroxychloroquine-induced apoptosis. Such Bax(-/-) Bak(-/-) cells manifest normal LMP, yet fail to undergo MMP and subsequent cell death. The data reported herein indicate that LMP does not suffice to trigger caspase activation and that Bax/Bak-dependent MMP is a critical step of LMP-induced cell death.
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“In other experimental settings, however, lysosomes are permeabilized before mitochondria [752, 760, 761], via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by the activation of its pore-forming activity [762–765].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [761]
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Research works printed but not linked: 1
- Boya P, Andreau K, Poncet D, Zamzami N, Perfettini JL, Metivier D, Ojcius DM, Jäättelä M and Kroemer G . (in press).
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Metadata
- Authors
- Boya, P., Gonzalez-Polo, R.-A., Poncet, D., Andreau, K., Vieira, H. L., Roumier, T., Perfettini, J.-L., & Kroemer, G.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Kroemer, Guido
- Venue
- Oncogene
- Published
- 2003-06-17
- Volume
- 22
- Issue
- 25
- Pages
- 3927-3936
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2073788301
- Cited by
- 385
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 16 · 2023: 7 · 2022: 17 · 2021: 19 · 2020: 23 · 2019: 19 · 2018: 25 · 2017: 15 · 2016: 20 · 2015: 26 · 2014: 11 · 2013: 26 · 2012: 19
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- hydroxychloroquine, lysosomal membrane permeabilization, mitochondrial membrane permeabilization, Bax, Bak, cytochrome c release, caspase activation, Bcl-xL, Bcl-2, mitochondrial membrane potential, mouse embryonic fibroblasts
- MeSH terms
- Amino Acid Chloromethyl Ketones, Animals, Anti-Bacterial Agents, Cell Line, Enzyme Activation, HeLa Cells, Humans, Hydroxychloroquine, Intracellular Membranes, Lysosomes, Membrane Proteins, Mitochondria, Permeability, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Signal Transduction, Cysteine Proteinase Inhibitors, Apoptosis, Mice, Knockout, Macrolides, Jurkat Cells, Proto-Oncogene Proteins c-bcl-2, Genes, bcl-2, Caspases, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, bcl-2-Associated X Protein, Mice, Rats
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