Activated BAX/BAK enable mitochondrial inner membrane permeabilisation and mtDNA release during cell death

Joel S. Riley, Giovanni Quarato, 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 journalArticlepeer-review

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 signaling. 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 signaling pathway. Strikingly, 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 over time. 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 can occur during cell death in a BAX/BAK-dependent manner. Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase-independent cell death.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Feb 26 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Activated BAX/BAK enable mitochondrial inner membrane permeabilisation and mtDNA release during cell death'. Together they form a unique fingerprint.

Cite this