Mitochondrial outer membrane integrity regulates a ubiquitin-dependent NF-kB 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, causing 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 remain poorly defined. Here, 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-kB 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, whereby permeabilised mitochondria initiate NF-?B signalling. This may be important for the various pathophysiological functions of MOMP-associated inflammation.