Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response

Vringer, E. et al. (2024) Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response. EMBO Journal, 43(6), pp. 904-930. (doi: 10.1038/s44318-024-00044-1) (PMID:38337057) (PMCID:PMC10943237)

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Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.

Item Type:Articles
Additional Information:This research was supported by funding from the Cancer Research UK [(DRCNPG-Jun22\100011 and A20145; S.W.G.T.)(A29256; D.T.H.)( (DRCNPG-Jun22\100007 and EDDPGM-Nov21\100001; DJM). Stand Up to Cancer campaign for CRUK A29800 to S.Z.; A31287 to CRUK Beatson Institute, A18076 to CRUK Glasgow Centre, A17196 to CRUK Beatson Institute Advanced Technology Facilities. R.H. is supported by a fellowship from the Swiss National Science Foundation and Novartis Foundation for Medical-Biological Research H.W. is supported by an Alexander von Humboldt Foundation Professorship Award, a Cancer Research UK Programme Grant (A27323), a Wellcome Trust Investigator Award (214342/Z/18/Z), a Medical Research Council Grant (MR/S00811X/1) and three collaborative research centre grants funded by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): SFB1399, Project C06; SFB1530-455784452, Project A03; and SFB1403–414786233. M.G-H. is supported by the LEO foundation and The Novo Nordisk Foundation (NNF20OC0059392).
Keywords:Mitochondria, cell death, inflammation, NF-κB, ubiquitin.
Glasgow Author(s) Enlighten ID:Heilig, Dr Rosalie and Lilla, Dr Sergio and Zanivan, Professor Sara and Riley, Dr Joel and Murphy, Professor Daniel and Tait, Professor Stephen and Vringer, Esmee and Huang, Professor Danny and Cloix, Dr Catherine and Skalka, Dr George and Montes Gomez, Mr Alfredo
Creator Roles:
Vringer, E.Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing
Heilig, R.Data curation, Formal analysis, Validation, Investigation, Writing – review and editing
Riley, J.Investigation, Methodology, Writing – review and editing
Cloix, C.Investigation, Methodology, Writing – review and editing
Skalka, G.Data curation, Formal analysis, Investigation
Montes-Gómez, A.Formal analysis
Lilla, S.Investigation, Methodology, Writing – review and editing
Walczak, P.Resources, Methodology, Writing – review and editing
Murphy, D.Funding acquisition
Huang, D.Data curation, Methodology, Writing – original draft, Writing – review and editing
Tait, S.Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing – original draft, Writing – review and editing
Authors: Vringer, E., Heilig, R., Riley, J. S., Black, A., Cloix, C., Skalka, G., Montes-Gómez, A. E., Aguado, A., Lilla, S., Walczak, H., Gyrd-Hansen, M., Murphy, D. J., Huang, D. T., Zanivan, S., and Tait, S. W.G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN (Online):1460-2075
Copyright Holders:Copyright: © The Author(s) 2024
First Published:First published in 43(6): 904-930
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
316271Understanding and targeting cell death oncogenicityStephen TaitCancer Research UK (CRUK)DRCNPG-Jun22\100011SCS - Therapeutic Science Research
172007Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)C40872/A20145School of Cancer Sciences
315764Integrated analysis from mouse to man for Early detection of Mesothelioma.Daniel MurphyCancer Research UK (CRUK)EDDPGM-Nov21\100001SCS - Beatson Institute for Cancer Research
190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076School of Cancer Sciences