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Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death.
- Source :
-
Molecular cell [Mol Cell] 2015 Mar 05; Vol. 57 (5), pp. 860-872. Date of Electronic Publication: 2015 Feb 19. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis drug effects
Biphenyl Compounds pharmacology
Blotting, Western
Caspases metabolism
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p19 deficiency
Cyclin-Dependent Kinase Inhibitor p19 genetics
Dose-Response Relationship, Drug
Embryo, Mammalian cytology
Fibroblasts drug effects
Fibroblasts metabolism
HCT116 Cells
HeLa Cells
Histones metabolism
Humans
MCF-7 Cells
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Nitrophenols pharmacology
Permeability
Piperazines pharmacology
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 metabolism
Staurosporine pharmacology
Sulfonamides pharmacology
Time Factors
Apoptosis physiology
DNA Damage
Genomic Instability
Mitochondrial Membranes physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 57
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 25702873
- Full Text :
- https://doi.org/10.1016/j.molcel.2015.01.018