Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage

Kai Cao, Joel S Riley, Rosalie Heilig, Alfredo E Montes-Gómez, Esmee Vringer, Kevin Berthenet, Catherine Cloix, Yassmin Elmasry, David G Spiller, Gabriel Ichim, Kirsteen J Campbell, Andrew P Gilmore, Stephen W G Tait

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.

Original languageEnglish
Pages (from-to)1211-1225.e6
JournalDevelopmental cell
Volume57
Issue number10
DOIs
Publication statusPublished - 23 May 2022

Keywords

  • Apoptosis/genetics
  • Apoptosis Regulatory Proteins/genetics
  • Caspases/metabolism
  • DNA Damage
  • Genomic Instability
  • Humans
  • Mitochondrial Dynamics
  • bcl-2-Associated X Protein/metabolism

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