Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

• Published in: The EMBO journal 2018-09, Vol.37 (17), p.n/a
• Main Authors: Riley, Joel S, Quarato, Giovanni, Cloix, Catherine, Lopez, Jonathan, O'Prey, Jim, Pearson, Matthew, Chapman, James, Sesaki, Hiromi, Carlin, Leo M, Passos, João F, Wheeler, Ann P, Oberst, Andrew, Ryan, Kevin M, Tait, Stephen WG
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bacterial proteins; BAX/BAK; Caspase; Cell activation; Cell death; Cell Line, Tumor; cGAS‐STING; Cytoplasm; Cytosol; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; EMBO07; EMBO20; EMBO37; Extrusion; Humans; Immunogenicity; Major outer membrane protein; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Membranes - metabolism; Mortality; mtDNA; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Permeability; Pore formation; Pores; Porosity; Signal transduction; Signaling; Widening
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201899238

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. Synopsis BAX/BAK pore formation ruptures the outer mitochondrial membrane in apoptotic cells while the inner membrane was thought to remain intact. New data show that permeabilisation of the mitochondrial inner membrane induces mitochondrial DNA release and signaling via cytosolic cGAS‐STING. Apoptotic mitochondrial outer membrane permeabilization (MOMP) induces widening pores in the mitochondrial outer membrane in a BAX/BAK‐dependent manner. Mitochondrial inner membrane is extruded through widening BAX pores. Mitochondrial inner membrane permeabilization (MIMP) enables mtDNA release into the cytoplasm and activation of the cGAS‐STING signaling pathway. Graphical Abstract The formation of BAX/BAK pores in apoptotic cells triggers extrusion of mitochondrial DNA through the inner mitochondria membrane, thereby activating cytosolic cGAS/STING signalling.