Figure 4.

Mitochondrial ROS and innate immunity. mtROS is produced at complexes I and III of the ETC in response to hypoxia, changes in substrate availability, and abnormal mitochondrial or cellular conditions. mtROS plays a role in coordinating innate immune responses, including antiviral signaling through the RLRs-MAVS, antimicrobial responses through the NLRP3 inflammasome and TLR pathways, and necroptosis through GSDMD. The cellular metabolism regulator AMPK helps to maintain a balance of mtROS and promote antimicrobial responses by inhibiting their generation, while HIF1-α enhances their production. AMPK also regulates the activation of the NLRP3 inflammasome by suppressing mtROS and promoting autophagy, which ERRα regulates through post-translational and transcriptional mechanisms. Additionally, the key regulator of mitophagy, Parkin, controls mtROS production and the activation of the NLRP3 inflammasome. Finally, increased cytosolic mtROS have been found to drive the mitochondrial localization of GSDMD, leading to the formation of a mitochondrial GSDMD pore and the acceleration of necroptosis.