Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis.

Autor: Riley JS; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Quarato G; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Cloix C; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Lopez J; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., O'Prey J; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Pearson M; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK., Chapman J; 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., Sesaki H; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Carlin LM; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Passos JF; 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.; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Wheeler AP; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK., Oberst A; Department of Immunology, University of Washington, Seattle, WA, USA.; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, USA., Ryan KM; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Tait SW; Cancer Research UK Beatson Institute, Glasgow, UK stephen.tait@glasgow.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2018 Sep 03; Vol. 37 (17). Date of Electronic Publication: 2018 Jul 26.
DOI: 10.15252/embj.201899238
Abstrakt: 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.
(© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE