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Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

Lookup NU author(s): Dr James Chapman, Dr Joao Passos

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.


Publication metadata

Author(s): Riley JS, Quarato G, Cloix C, Lopez J, O'Prey J, Pearson M, Chapman J, Sesaki H, Carlin LM, Passos JF, Wheeler AP, Oberst A, Ryan KM, Tait SWG

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2018

Volume: 37

Issue: 17

Print publication date: 03/09/2018

Online publication date: 26/07/2018

Acceptance date: 18/06/2018

Date deposited: 28/09/2018

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Wiley-VCH Verlag

URL: https://doi.org/10.15252/embj.201899238

DOI: 10.15252/embj.201899238


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