Ichim, G. et al. (2015) Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Molecular Cell, 57(5), pp. 860-872. (doi: 10.1016/j.molcel.2015.01.018) (PMID:25702873) (PMCID:PMC4352766)
|
Text
102955.pdf - Published Version Available under License Creative Commons Attribution. 3MB |
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | A correction to this article is available at https://doi.org/10.1016/j.molcel.2015.05.028. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Blyth, Professor Karen and Murphy, Professor Daniel and Ichim, Dr Gabriel and Riley, Dr Joel and Haller, Ms Martina and Ahmed, Dr Shafiq and Athineos, Mr Dimitris and Tait, Professor Stephen and Lopez, Dr Jonathan and Mason, Miss Susan and Chalmers, Professor Anthony |
| 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., and Tait, S. W.G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Molecular Cell |
| Publisher: | Cell Press |
| ISSN: | 1097-2765 |
| ISSN (Online): | 1097-4164 |
| Published Online: | 19 February 2015 |
| Copyright Holders: | Copyright © 2015 The Authors |
| First Published: | First published in Molecular Cell 57(5):860-872 |
| Publisher Policy: | Reproduced under a Creative Commons License |
| Related URLs: |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric