Microglia are immune cells in the central nervous system and contribute to brain homeostasis. Recently, it has been reported that mitochondrial dysfunction in the brain is observed with aging. However, influence of mitochondrial dysfunction in microglial function is unknown. We previously reported that rotenone-induced mitochondria DNA (mtDNA) leakage into cytosol enhances the production of interferon (IFN)-β by an inflammatory stimulus (lipopolysaccharide: LPS). Therefore, the current study focused on the cytosolic mtDNA to clarify the mechanisms underlying mitochondrial dysfunction-enhanced IFN-β production.
BV2 cells, a mouse microglial cell line, were used. Mitochondrial DNA was extracted from the cytosolic fraction at 3, 6, 18, and 24 hrs after rotenone treatment. The inhibitor of cyclic GMP-AMP synthase (cGAS) recognizing mtDNA was treated 6 hours before LPS treatment. Expression levels of mRNA and mtDNA were measured by real-time PCR. Leakage of mtDNA into the cytoplasm was increased 18 and 24, but not 3 and 6, hrs after rotenone treatment. Furthermore, rotenone-enhanced IFN-β mRNA production was only observed at the time point of mtDNA leakage. In addition, cGAS inhibitor significantly suppressed the IFNβ mRNA enhancement.As a results, mitochondrial dysfunction in microglia enhances IFN-β production via the mtDNA-cGAS pathway.