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

Abstract

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