Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

EMBO J. 2018 Sep 3;37(17):e99238. doi: 10.15252/embj.201899238. Epub 2018 Jul 26.


During apoptosis, pro-apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP Such caspase-independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS-STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS-STING signalling pathway. Using super-resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP In a temporal manner, we find that following MOMP, BAX/BAK-mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK-dependent MOMP Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase-independent cell death.

Keywords: BAX/BAK; apoptosis; cGAS‐STING; mitochondria; mtDNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line, Tumor
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Permeability


  • DNA, Mitochondrial
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse