Limited Mitochondrial Permeabilization Causes DNA Damage and Genomic Instability in the Absence of Cell Death
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During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term "minority MOMP." Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis.
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When MOMP affects a limited number of mitochondria, the consequent sublethal activation of caspases does not precipitate RCD but promotes genomic instability.
“In addition, when MOMP affects a limited number of mitochondria, the consequent sublethal activation of caspases does not precipitate RCD but promotes genomic instability [226].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [226]
At least some cells exposed to transient apoptotic stimuli appear to survive MOMP affecting a limited number of mitochondria and the partial activation of executioner caspases by a process called anastasis.
“Finally, at least some cells exposed to transient apoptotic stimuli appear to survive MOMP affecting a limited number of mitochondria and the partial activation of executioner caspases by a hitherto poorly characterized process called anastasis (most likely constituting a robust adaptative response upstream of the boundary between cellular life and death) [226–228].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [226]
Under sub-lethal stress, a small subset of mitochondria can undergo MOMP without causing cell death, a phenomenon called minority MOMP.
“However, it has been shown that in conditions of sub-lethal stress, a small subset of mitochondria undergo MOMP without inducing cell death, a phenomenon called minority MOMP (miMOMP) (Ichim et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Ichim et al., 2015
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Self-citation
- Authors
- Ichim, G., Lopez, J., Ahmed, S. U., Muthalagu, N., Giampazolias, E., Delgado, M. E., Haller, M., Riley, J. S., Mason, S. M., Athineos, D., Parsons, M. J., van de Kooij, B., Bouchier-Hayes, L., Chalmers, A. J., Rooswinkel, R. W., Oberst, A., Blyth, K., Rehm, M., Murphy, D. J., & Tait, S. W. G.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Glasgow (GB)
- Royal College of Surgeons in Ireland (IE)
- Baylor College of Medicine (US)
- The Netherlands Cancer Institute (NL)
- University of Washington (US)
- Corresponding author
- Tait, Stephen W.G.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 57
- Issue
- 5
- Pages
- 860-872
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4352766
- OpenAlex
- W2099583458
- Cited by
- 479
- References
- 42
- Citations by year
- 2026: 49 · 2025: 48 · 2024: 57 · 2023: 45 · 2022: 58 · 2021: 43 · 2020: 42 · 2019: 36 · 2018: 33 · 2017: 32 · 2016: 22 · 2015: 11
- FWCI
- 14.19
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-06-04)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Sunderland Repository (University of Sunderland) (acceptedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Cancer Research UK (22311)
- Royal Society
- European Commission
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BB/K008374/1)
- National Institute of Allergy and Infectious Diseases (R01AI108685)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial outer membrane permeabilization, apoptosis, caspase activation, cytochrome c release, DNA damage, genomic instability, cell transformation, carcinogenesis, tumor suppression
- MeSH terms
- Animals, Biphenyl Compounds, DNA Damage, Dose-Response Relationship, Drug, Embryo, Mammalian, Fibroblasts, HeLa Cells, Histones, Humans, Mice, Inbred C57BL, Nitrophenols, Permeability, Piperazines, Sulfonamides, Time Factors, Blotting, Western, Apoptosis, Mice, Knockout, Microscopy, Confocal, Proto-Oncogene Proteins c-bcl-2, Staurosporine, Caspases, Genomic Instability, HCT116 Cells, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p19, Mitochondrial Membranes, MCF-7 Cells
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