This study investigates the activation of the NLRP3 inflammasome during apoptosis, focusing on the role of oxidized mitochondrial DNA (mtDNA). The authors found that in the presence of signal 1 (NF-κB), mitochondrial apoptotic signaling activates the NLRP3 inflammasome, leading to the production of interleukin-1β (IL-1β). They demonstrated that secondary signal activators like ATP induce mitochondrial dysfunction and apoptosis, resulting in the release of oxidized mtDNA into the cytosol. This mtDNA binds to and activates the NLRP3 inflammasome. The anti-apoptotic protein Bcl-2 was shown to inversely regulate mitochondrial dysfunction and NLRP3 inflammasome activation. The study also revealed that mtDNA directly induces NLRP3 inflammasome activation, as macrophages lacking mtDNA had significantly reduced IL-1β production. Additionally, the oxidized nucleoside 8-OH-dG competitively inhibited the binding of oxidized mtDNA to the NLRP3 inflammasome and prevented IL-1β secretion. These findings provide a missing link between apoptosis and inflammasome activation, highlighting the importance of mtDNA in this process.This study investigates the activation of the NLRP3 inflammasome during apoptosis, focusing on the role of oxidized mitochondrial DNA (mtDNA). The authors found that in the presence of signal 1 (NF-κB), mitochondrial apoptotic signaling activates the NLRP3 inflammasome, leading to the production of interleukin-1β (IL-1β). They demonstrated that secondary signal activators like ATP induce mitochondrial dysfunction and apoptosis, resulting in the release of oxidized mtDNA into the cytosol. This mtDNA binds to and activates the NLRP3 inflammasome. The anti-apoptotic protein Bcl-2 was shown to inversely regulate mitochondrial dysfunction and NLRP3 inflammasome activation. The study also revealed that mtDNA directly induces NLRP3 inflammasome activation, as macrophages lacking mtDNA had significantly reduced IL-1β production. Additionally, the oxidized nucleoside 8-OH-dG competitively inhibited the binding of oxidized mtDNA to the NLRP3 inflammasome and prevented IL-1β secretion. These findings provide a missing link between apoptosis and inflammasome activation, highlighting the importance of mtDNA in this process.