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Mol Cell. 2015 Mar 5;57(5):860-872. doi: 10.1016/j.molcel.2015.01.018. Epub 2015 Feb 19.

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

Author information

1
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
3
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland, Baylor College of Medicine, Houston, TX 77030, USA.
4
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
5
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics-Hematology, Baylor College of Medicine, Houston, TX 77030, USA.
6
Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands.
7
Department of Immunology, University of Washington, 750 Republican Street, Seattle, WA 98109, USA.
8
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Electronic address: stephen.tait@glasgow.ac.uk.

Erratum in

  • Mol Cell. 2015 Jun 4;58(5):900.

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.

Comment in

PMID:
25702873
PMCID:
PMC4352766
DOI:
10.1016/j.molcel.2015.01.018
[Indexed for MEDLINE]
Free PMC Article

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