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

Mitochondria are often essential for apoptosis through mitochondrial outer membrane permeabilization (MOMP). This central event enables cytochrome c release leading to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory, for instance, by enabling mitochondrial DNA-dependent activation of cGAS-STING signalling. Alongside having emerging functions in health and disease, MOMP associated inflammation can also elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell counteracts this remains poorly defined. We find that upon MOMP, mitochondria are ubiquitylated in a promiscuous manner targeting proteins localised to both inner and outer mitochondrial membranes. Mitochondrial ubiquitylation serves to recruit the essential adaptor molecule, NEMO, leading to activation of pro-inflammatory NF-κB signalling. We find that disruption of mitochondrial outer membrane integrity through different means leads to engagement of a similar pro-inflammatory signalling platform. Thus, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling. This event may be important for the various pathophysiological functions of MOMP-associated inflammation. ### Competing Interest Statement SWGT consults for Exo Therapeutics The raw files and the MaxQuant search results files have been deposited to the ProteomeXchange Consortium ([Deutsch et al , 2020][1]) via the PRIDE partner repository ([Perez-Riverol et al , 2022][2]) with the dataset identifier PXD040192. Data are available via ProteomeXchange with identifier PXD040192. For reviewer access: Username: reviewer_pxd040192@ebi.ac.uk Password: YDEFnxY5 [1]: #ref-10 [2]: #ref-33