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.若无法通过线粒体自噬（mitophagy）清除受损线粒体，将破坏机体生理功能，并可能通过炎症级联反应触发损伤信号通路，然而这些通路的交叉调控机制目前仍未明确。本研究发现，核因子κB（NF-κB）的必需调节蛋白NEMO以帕金蛋白（Parkin）依赖的方式被招募至受损线粒体，其招募时序与结构同源的线粒体自噬接头蛋白视神经蛋白（OPTN）的招募时序高度相似。完成招募后，NEMO会形成与OPTN不同的相分离凝聚体（phase-separated condensates），但可与p62/SQSTM1发生共定位。而NEMO的招募会进一步招募具有催化活性的磷酸化IKKβ（phospho-IKKβ）亚基，启动NF-κB信号通路并促进炎症细胞因子的表达上调。这与NEMO潜在的神经炎症功能相符：在氧化应激刺激下，原代星形胶质细胞（primary astrocytes）中的NEMO会被招募至线粒体。上述研究结果表明，受损的泛素化线粒体可作为细胞内平台启动先天免疫信号通路，促进足以激活NF-κB信号的活化IKK复合物的形成。本研究提出，线粒体自噬与NF-κB信号通路可作为平行通路，以响应线粒体应激。