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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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Cites
Green, D. R., & Reed, J. C. (1998) · Science · doi:10.1126/science.281.5381.1309 · Cited by 9,051
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · cited 1×
“…of the proapoptotic genes Bax and Bak (whose products induce MMP) confers a broad cytoprotection including against nuclear DNA damage and ER stress (Zamzami et al., 1998; Vogelstein et al., 2000; Ferri and Kroemer, 2001; Wei et al., 2001; Boya et al., 2002; Reed, 2002; Zamzami and Kroemer, 2003).”
BackgroundProapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988
Mitochondrial control of cell death
Kroemer, G., & Reed, J. C. (2000) · Nature Medicine · doi:10.1038/74994 · Cited by 3,103
Self-citationde Duve, C., & Wattiaux, R. (1966) · Annual Review of Physiology · doi:10.1146/annurev.ph.28.030166.002251 · Cited by 3,033 · cited 1×
“…this paper reinforce the general idea that MMP is rate limiting for cell death induction (Boya et al., 2003), even when apoptosis has initially been triggered by permeabilizing the ‘suicide bags’, as lysosomes have been initially nick-named (De Duve and Wattiaux, 1966; Lockshin and Zakeri, 2001).”
BackgroundNicholson, D. W., & Thornberry, N. A. (1997) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(97)01085-2 · Cited by 2,418
Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S. A., Petit, P. X., Mignotte, B., & Kroemer, G. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.2.367 · Cited by 1,567
Self-citationOrganelle-specific initiation of cell death pathways
Ferri, K. F., & Kroemer, G. (2001) · Nature Cell Biology · doi:10.1038/ncb1101-e255 · Cited by 1,455
Self-citationEnforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis
Gross, A., Jockel, J., Wei, M. C., & Korsmeyer, S. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.14.3878 · Cited by 1,095
Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis
Daugas, É., Susín, S. A., Zamzami, N., Ferri, K. F., Irinopoulou, T., Larochette, N., Prévost, M., Leber, B. F., Andrews, D. W., Penninger, J. M., et al. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.5.729 · Cited by 777
Self-citation
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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Self-citationOxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
Shimada, K., Crother, T. R., Karlin, J., Dagvadorj, J., Chiba, N., Chen, S., Ramanujan, V. K., Wolf, A. J., Vergnes, L., Ojcius, D. M., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.01.009 · Cited by 2,282
Inhibition of Macroautophagy Triggers Apoptosis
Boya, P., González‐Polo, R. A., Casares, N., Perfettini, J., Dessen, P., Larochette, N., Métivier, D., Meley, D., Souquère, S., Yoshimori, T., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.3.1025-1040.2005 · Cited by 1,669
Self-citationLysosomal membrane permeabilization in cell death
Boya, P., & Kroemer, G. (2008) · Oncogene · doi:10.1038/onc.2008.310 · Cited by 1,456
Self-citationAutophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment
Sui, X., Chen, R. B., Wang, Z., Huang, Z., Kong, N., Zhang, M., Han, W., Lou, F., Yang, J., Zhang, Q., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.350 · Cited by 1,255
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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