Abstract: Mitochondria are important organelles for cellular metabolism and homeostasis, and their abnormalities are implicated in various diseases. Since mitochondria originate from protobacterium, their components are easily recognized by pathogen sensors called pattern-recognition receptors as foreign substances in the cytoplasm. This is prominent for mitochondrial DNA (mtDNA) which has different properties from nuclear DNA, such as low, if any, methylation status, vulnerability to oxidation due to the proximity to the oxidative phosphorylation machinery, and its circular structure. Recent studies indicate that perturbations in mitochondrial function and homeostasis cause mtDNA to leak into the cytoplasm, where it triggers the innate immune response (West and Shadel, 2017). Although inflammatory response is a cellular strategy to resist viral infections, it can also lead to undesirable outcomes by damaging own cells and tissues. Recently, we found that mtDNA leak into the cytoplasm in Parkinson’s disease (PD) models of human cells and zebrafish. Furthermore, we revealed that the leaked mtDNA is detected by a viral DNA sensor interferon gamma inducible protein 16 (IFI16), which has not been implicated in mtDNA recognition, and triggers inflammatory responses. Decreasing mtDNA sensor or overexpression of mtDNA-degrading enzymes in the PD model eliminated cytosolic mtDNA and suppressed the inflammatory response as well as neurodegeneration. Importantly, accumulation of mtDNA and IFI16 in the cytoplasm was also observed in autopsy brains of human PD patients, pointing to pathological relevance (Matsui et al., 2021). In this perspective, we will first overview the various cases and pathways by which mtDNA leakage triggers inflammatory responses, and then in particular look into how mtDNA-mediated inflammation can explain the pathogenesis of PD, discussing the ways to ameliorate the pathological conditions.