Targeting Mitochondrial Genome Maintenance to Modulate Interferon Responses

Mitochondrial DNA (mtDNA) released into the cytosol can activate innate immune pathways and drive type I interferon responses. In our work, we investigate how the DNA polymerase theta (Polθ) contributes to mitochondrial genome maintenance and controls the immunogenic fate of damaged mtDNA. We will present recent findings suggesting that Polθ-dependent processing of mtDNA influences activation of the cGAS–STING pathway and interferon signaling following genotoxic stress. These results highlight mitochondrial DNA maintenance as a potential target to modulate inflammatory responses in contexts such as cancer therapy, aging, and neuroinflammation.