Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

• Joel S Riley ^[1] ; Giovanni Quarato ^[2] ; Catherine Cloix ^[1] ; Jonathan Lopez ^[7] ; Jim O'Prey ^[1] ; Matthew Pearson ^[3] ; James Chapman ^[4] ; Hiromi Sesaki ^[5] ; Leo M Carlin ^[1] ; João F Passos ^[4] ; Ann P Wheeler ^[3] ; Andrew Oberst ^[6] ; Kevin M Ryan ^[1] ; Stephen WG Tait ^[1]
  1. [1] University of Glasgow

     University of Glasgow

     Reino Unido

     
  2. [2] St. Jude Children's Research Hospital

     St. Jude Children's Research Hospital

     Estados Unidos

     
  3. [3] University of Edinburgh

     University of Edinburgh

     Reino Unido

     
  4. [4] Newcastle University

     Newcastle University

     Reino Unido

     
  5. [5] Johns Hopkins University

     Johns Hopkins University

     Estados Unidos

     
  6. [6] University of Washington

     University of Washington

     Estados Unidos

     
  7. [7] 1 Cancer Research UK Beatson Institute Glasgow UK; 2 Institute of Cancer Sciences University of Glasgow Glasgow UK; 10Present address: UMR INSERM 1052 CNRS 5286 Cancer Research Centre of Lyon (CRCL) Léon Bérard Centre University of Lyon Lyon France

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 17, 2018
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • 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.