Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death

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)

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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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmed, Dr Shafiq and Blyth, Dr Karen and Murphy, Dr Daniel and Ichim, Dr Gabriel and Athineos, Mr Dimitris and Riley, Dr Joel and Tait, Professor Stephen and Lopez, Dr Jonathan and Mason, Miss Susan and Chalmers, Professor Anthony and Haller, Ms Martina
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 > Institute 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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607521A new approach to understanding mitochondrial functions in cell death, autophagy and beyondStephen TaitBiotechnology and Biological Sciences Research Council (BBSRC)BB/K008374/1RI CANCER SCIENCES
631931Regulating cell death after mitochondrial permeabilization: putting the bullet back in the gunStephen TaitEuropean Molecular Biology Organisation (EMBO)ALTF 55-2013RI CANCER SCIENCES