This article explores the role of Parkin and PINK1 in mitigating STING-induced inflammation, which is linked to Parkinson’s disease (PD). Parkin and PINK1 are E3 ubiquitin ligase and ubiquitin kinase, respectively, and they work together in a biochemical pathway to remove damaged mitochondria through a process called mitophagy. Despite the lack of substantial PD-related phenotypes in mice lacking these proteins, the study shows that both Parkin and PINK1 deficiency leads to increased inflammation, particularly after exhaustive exercise (EE) and in aged Parkin−/−:Mutator mice, which accumulate mitochondrial DNA mutations. The inflammatory response is significantly reduced when STING, a key regulator of the type I interferon response to cytosolic DNA, is absent. This suggests that inflammation may contribute to neuronal loss in PD. The study also found that Parkin and PINK1 deficiency leads to elevated levels of inflammatory cytokines in both mice and humans, with human Parkin heterozygotes showing increased levels of IL-6, IL-1β, CCL2, and CCL4, similar to idiopathic PD patients. The findings indicate that Parkin and PINK1-mediated mitophagy may help prevent the release of damage-associated molecular patterns (DAMPs), which can activate innate immunity. The study further shows that STING activation by mitochondrial DNA (mtDNA) leads to an increase in type I interferon response, which is mitigated by the loss of STING. The results support a model where mitophagy prevents inflammation and neurodegeneration by clearing damaged mitochondria, thus reducing cytosolic and circulating mtDNA. The study also highlights that STING-mediated inflammation contributes to the motor defects observed in Parkin−/−;Mutator mice, and that its absence rescues these defects. Overall, the study underscores the importance of Parkin and PINK1 in maintaining mitochondrial homeostasis and preventing inflammation in PD.This article explores the role of Parkin and PINK1 in mitigating STING-induced inflammation, which is linked to Parkinson’s disease (PD). Parkin and PINK1 are E3 ubiquitin ligase and ubiquitin kinase, respectively, and they work together in a biochemical pathway to remove damaged mitochondria through a process called mitophagy. Despite the lack of substantial PD-related phenotypes in mice lacking these proteins, the study shows that both Parkin and PINK1 deficiency leads to increased inflammation, particularly after exhaustive exercise (EE) and in aged Parkin−/−:Mutator mice, which accumulate mitochondrial DNA mutations. The inflammatory response is significantly reduced when STING, a key regulator of the type I interferon response to cytosolic DNA, is absent. This suggests that inflammation may contribute to neuronal loss in PD. The study also found that Parkin and PINK1 deficiency leads to elevated levels of inflammatory cytokines in both mice and humans, with human Parkin heterozygotes showing increased levels of IL-6, IL-1β, CCL2, and CCL4, similar to idiopathic PD patients. The findings indicate that Parkin and PINK1-mediated mitophagy may help prevent the release of damage-associated molecular patterns (DAMPs), which can activate innate immunity. The study further shows that STING activation by mitochondrial DNA (mtDNA) leads to an increase in type I interferon response, which is mitigated by the loss of STING. The results support a model where mitophagy prevents inflammation and neurodegeneration by clearing damaged mitochondria, thus reducing cytosolic and circulating mtDNA. The study also highlights that STING-mediated inflammation contributes to the motor defects observed in Parkin−/−;Mutator mice, and that its absence rescues these defects. Overall, the study underscores the importance of Parkin and PINK1 in maintaining mitochondrial homeostasis and preventing inflammation in PD.