TNFα-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation
Abstract
When NF-κB activation or protein synthesis is inhibited, tumor necrosis factor alpha (TNFα) can induce apoptosis via Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP) leading to caspase-3 activation. Additionally, previous studies have implicated lysosomal membrane permeability (LMP) and reactive oxygen species (ROS) as early steps of TNFα-induced apoptosis. However, how these two events connect to MOMP and caspase-3 activation has been largely debated. Here we present the novel finding that TNFα/cycloheximide (CHX)-induced LMP, the release of lysosomal cathepsins and ROS formation do not occur upstream but downstream of MOMP and require the caspase-3-mediated cleavage of the p75 NDUFS1 subunit of respiratory complex I. Both a caspase non-cleavable p75 mutant and the mitochondrially localized antioxidant MitoQ prevent TNFα/CHX-induced LMP and partially interfere with apoptosis induction. Moreover, LMP is completely blocked in Bax/Bak-/-, Apaf-1-/-, caspase-9-/- and caspase-3/7-/- cells. Thus, after MOMP, active caspase-3 exerts a feedback action on complex I to produce ROS. ROS then provoke LMP, cathepsin release and further caspase activation to amplify TNFα apoptosis signaling.
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In some circumstances, LMP appears to occur downstream of MOMP as a result of apoptotic signaling, constituting an epiphenomenon of intrinsic apoptosis.
“In some circumstances, LMP appears to occur downstream of MOMP as a result of apoptotic signaling, de facto constituting an epiphenomenon of intrinsic apoptosis [757–759].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [757]
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Role of lysosomes in oxidative stress induced regulated cell death
Nagakannan, P. (2020) · Mspace (University of Manitoba)
- Authors
- Huai, J., Vögtle, F.-N., Jöckel, L., Li, Y., Kiefer, T., Ricci, J.-E., & Borner, C.
- Affiliations
- University of Freiburg (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Inserm (FR)
- Corresponding author
- Huai, Jisen
- Borner, Christoph
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2013-01-01
- Volume
- 126
- Issue
- Pt 17
- Pages
- 4015-25
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2168983728
- Cited by
- 43
- References
- 59
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 7 · 2014: 5 · 2013: 3
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-09-JCJC-0003)
- 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 › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- TNFα-induced apoptosis, lysosomal membrane permeability, mitochondrial outer membrane permeabilization, caspase-3, mitochondrial complex I, reactive oxygen species, Bax, Bak, Apaf-1, MitoQ, cycloheximide, caspase-7, caspase-9
- MeSH terms
- Animals, Cathepsin B, Cell Membrane, Cell Membrane Permeability, Cycloheximide, Enzyme Activation, HeLa Cells, Humans, Mice, Inbred C57BL, Mitochondria, NADH Dehydrogenase, Organophosphorus Compounds, Protein Synthesis Inhibitors, Tumor Necrosis Factor-alpha, Ubiquinone, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Electron Transport Complex I, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mitochondrial Membranes, Mice, Caspase 3, Caspase 7, Caspase 9, Apoptotic Protease-Activating Factor 1, Cathepsin L
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