Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

Joel S. Riley, Giovanni Quarato, Catherine Cloix, Jonathan Lopez, Jim O'Prey, Matthew Pearson, James Chapman, Hiromi Sesaki, Leo M. Carlin, João F. Passos, Ann P. Wheeler, Andrew Oberst, Kevin M. Ryan, Stephen W.G. Tait

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere99238
JournalEMBO Journal
Volume37
Issue number17
DOIs
StatePublished - Sep 3 2018

Keywords

  • BAX/BAK
  • apoptosis
  • cGAS-STING
  • mitochondria
  • mtDNA

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Riley, J. S., Quarato, G., Cloix, C., Lopez, J., O'Prey, J., Pearson, M., Chapman, J., Sesaki, H., Carlin, L. M., Passos, J. F., Wheeler, A. P., Oberst, A., Ryan, K. M., & Tait, S. W. G. (2018). Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO Journal, 37(17), [e99238]. https://doi.org/10.15252/embj.201899238