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

Ichim, G, Lopez, J, Ahmed, Shafiq, Muthalagu, N, Giampazolias, E, Delgado, E, Haller, Martina, Riley, Joel S, Mason, Susan, Athineos, Dimitris, Parsons, MJ, Kooij, BVD, Bouchier-Hayes, L, Chalmers, A, Rooswinkel, R, Oberst, A, Blyth, K, Rehm, M, Murphy, D and Tait, S (2015) Limited mitochondrial permeabilisation causes DNA-damage and genomic instability in the absence of cell death. Molecular Cell, 57 (5). pp. 860-872. ISSN 1097-2765

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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.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Depositing User: Paula Normington
Date Deposited: 12 Feb 2016 12:21
Last Modified: 04 Feb 2021 18:51
ORCID for Shafiq Ahmed: ORCID iD

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