2. Academic Validation
  3. Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response

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

  • EMBO J. 2024 Feb 9. doi: 10.1038/s44318-024-00044-1.
Esmee Vringer # 1 2,  Rosalie Heilig # 1 2,  Joel S Riley 1 2 3,  Annabel Black 1 2,  Catherine Cloix 1 2,  George Skalka 1 2,  Alfredo E Montes-Gómez 1 2,  Aurore Aguado 1 2,  Sergio Lilla 2,  Henning Walczak 4 5 6,  Mads Gyrd-Hansen 7,  Daniel J Murphy 1 2,  Danny T Huang 1 2,  Sara Zanivan 1 2,  Stephen Wg Tait 8 9
Affiliations

Affiliations

  • 1 Cancer Research UK Scotland Institute, Switchback Road, Glasgow, G61 1BD, UK.
  • 2 School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow, G61 1BD, UK.
  • 3 Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 4 Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
  • 5 CECAD Cluster of Excellence, University of Cologne, Cologne, Germany.
  • 6 Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • 7 Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
  • 8 Cancer Research UK Scotland Institute, Switchback Road, Glasgow, G61 1BD, UK. stephen.tait@glasgow.ac.uk.
  • 9 School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow, G61 1BD, UK. stephen.tait@glasgow.ac.uk.
  • # Contributed equally.
PMID: 38337057 DOI: 10.1038/s44318-024-00044-1
Abstract

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.

Keywords

Cell Death; Inflammation; Mitochondria; NF-κB; Ubiquitin.

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