Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-dependent Fashion
Open accessAbstract
A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax−/− Bak−/− double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum–targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization.
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In other experimental settings, lysosomes are permeabilized before mitochondria via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by activation of its pore-forming activity.
“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 [760]
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- Authors
- Boya, P., Andreau, K., Poncet, D., Zamzami, N., Perfettini, J.-L., Metivier, D., Ojcius, D. M., Jäättelä, M., & Kroemer, G.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- 1Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, F-94805 Villejuif, France
- Institut Pasteur (FR)
- 3Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark
- Corresponding author
- Kroemer, Guido
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2003-05-19
- Volume
- 197
- Issue
- 10
- Pages
- 1323-1334
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2193790
- OpenAlex
- W2044247344
- Cited by
- 483
- References
- 48
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 12 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 20 · 2019: 15 · 2018: 17 · 2017: 22 · 2016: 18 · 2015: 34 · 2014: 19 · 2013: 27 · 2012: 16
- FWCI
- 9.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Scholarly Commons (University of the Pacific) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- lysosomal membrane permeabilization, lysosomal cell death, quinolones, ciprofloxacin, norfloxacin, ultraviolet radiation, mitochondrial membrane permeabilization, cytochrome c release, Bax, Bak, Bcl-2, caspase-independent cell death, apoptosis, mitochondrial targeting, lysosomal destabilization
- MeSH terms
- Amino Acid Chloromethyl Ketones, Cell Membrane Permeability, Ciprofloxacin, HeLa Cells, Humans, Lysosomes, Membrane Proteins, Metalloendopeptidases, Mitochondria, Norfloxacin, Proto-Oncogene Proteins, Apoptosis, Reactive Oxygen Species, Proto-Oncogene Proteins c-bcl-2, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
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