Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling

Failure to clear damaged mitochondria via mitophagy disrupts physiological function and may initiate damage signaling via inflammatory cascades, though how these pathways intersect remains unclear. We discovered that NF-κB essential regulator NEMO is recruited to damaged mitochondria in a Parkin-dependent manner in a time-course similar to recruitment of the structurally-related mitophagy adaptor, OPTN. Upon recruitment, NEMO partitions into phase-separated condensates distinct from OPTN, but colocalizing with p62/SQSTM1. NEMO recruitment in turn recruits the active catalytic IKK component phospho-IKKb, initiating NF-κB signaling and the upregulation of inflammatory cytokines. Consistent with a potential neuroinflammatory role, NEMO is recruited to mitochondria in primary astrocytes upon oxidative stress. These findings suggest that damaged, ubiquitinated mitochondria serve as an intracellular platform to initiate innate immune signaling, promoting the formation of activated IKK complexes sufficient to activate NF-kB signaling. We propose that mitophagy and NF-κB signaling are initiated as parallel pathways in response to mitochondrial stress.