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

Failure to clear damaged mitochondria via mitophagy disrupts physiological<br> function and may initiate damage signaling via inflammatory cascades. However,<br> signaling mechanisms leading from impaired mitophagy to neuro-inflammation are<br> unclear. We discovered that NF-κB essential regulator NEMO is recruited to damaged<br> mitochondria in a Parkin- and p62/SQSTM1-dependent manner in a time-course similar<br> to recruitment of the structurally-related mitophagy receptor, OPTN. NEMO and p62<br> colocalize, partitioning into distinct domains from OPTN. Either depletion of p62 or<br> mutation of NEMO’s ubiquitin-binding domain abolishes NEMO recruitment, indicating<br> multifactorial interactions. The active catalytic IKK component phospho-IKKß colocalizes<br> with NEMO on damaged mitochondria, initiating NF-κB signaling and the upregulation of<br> inflammatory cytokines. These findings suggest that damaged mitochondria serve as an<br> intracellular platform for innate immune signaling by promoting the formation of activated<br> IKK complexes in a Parkin-dependent manner. We propose that mitophagy and NF-κB<br> signaling are competing pathways regulating the response to cellular stress.