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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Biphenyl Compounds / pharmacology
  • Blotting, Western
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p19 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p19 / genetics
  • DNA Damage*
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Genomic Instability*
  • HCT116 Cells
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • MCF-7 Cells
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Mitochondrial Membranes / physiology*
  • Nitrophenols / pharmacology
  • Permeability
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Staurosporine / pharmacology
  • Sulfonamides / pharmacology
  • Time Factors


  • ABT-737
  • Biphenyl Compounds
  • Cdkn2d protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p19
  • H2AX protein, human
  • Histones
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Caspases
  • Staurosporine