Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

Riley, J. S. et al. (2018) Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO Journal, 37(17), e99238. (doi: 10.15252/embj.201899238) (PMID:30049712) (PMCID:PMC6120664)

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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. 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.

Item Type:Articles
Additional Information:Funding for this work was from the BBSRC (grant BB/K008374/1) Cancer Research UK Programme Foundation Award (C40872/A20145; SWGT) and NIH grant GM123266 (HS).
Glasgow Author(s) Enlighten ID:O'Prey, Mr James and Riley, Dr Joel and Tait, Professor Stephen and Cloix, Dr Catherine and Ryan, Professor Kevin and Carlin, Dr Leo
Authors: Riley, J. S., Quarato, G., Cloix, C., Lopez, J., O'Prey, J., Pearson, M., Chapman, J., Sesaki, H., Carlin, L. M., Passos, J. F., Wheeler, A. P., Oberst, A., Ryan, K. M., and Tait, S. W.G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:EMBO Journal
ISSN (Online):1460-2075
Published Online:26 July 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in EMBO Journal 37(17):e99238
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607521A new approach to understanding mitochondrial functions in cell death, autophagy and beyondStephen TaitBiotechnology and Biological Sciences Research Council (BBSRC)BB/K008374/1RI CANCER SCIENCES
690911Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)20145RI CANCER SCIENCES