title: Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death.
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.
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ichim
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Shafiq U
authors.initials: SU
authors.lastname: Ahmed
authors.affiliation: 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.
authors.forename: Nathiya
authors.initials: N
authors.lastname: Muthalagu
authors.affiliation: 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.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giampazolias
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Delgado
authors.affiliation: 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.
authors.forename: Martina
authors.initials: M
authors.lastname: Haller
authors.affiliation: 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.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Riley
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mason
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Athineos
authors.affiliation: 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.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Parsons
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van de Kooij
authors.affiliation: 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.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bouchier-Hayes
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chalmers
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Rooswinkel
authors.affiliation: Department of Immunology, University of Washington, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
authors.affiliation: 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Stephen W G
authors.initials: SWG
authors.lastname: Tait
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000172:deficiency / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D042822:Genomic Instability; D045325:HCT116 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D051336:Mitochondrial Membranes / Q000502:physiology*; D009596:Nitrophenols / Q000494:pharmacology; D010539:Permeability; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; C468783:H2AX protein, human; D006657:Histones; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D020169:Caspases; D019311:Staurosporine