Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis |
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| Authors: | 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 WG Tait |
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| Institution: | 1. Cancer Research UK Beatson Institute, Glasgow, UK;2. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK;3. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA;4. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK;5. Ageing Research Laboratories, Newcastle University Institute for Ageing, LLHW Centre for Ageing and Vitality, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK;6. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;7. Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK;8. Department of Immunology, University of Washington, Seattle, WA, USA;9. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, USA |
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| 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. |
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| Keywords: | apoptosis BAX/BAK cGAS‐STING mitochondria mtDNA |
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