(Top) Loss of Lrrk2 in mouse macrophages increases DRP1 phosphorylation. This leads to an increase in the level of mitochondrial DNA (mtDNA; red bean-shaped structures) in the cytosol, which activates the cGAS/STING pathway. This, in turn, triggers the phosphorylation of transcription factors that activate the expression of interferon (IFN) response genes in the nucleus, which leads to a lowered response to interferon from these cells. In this situation, antioxidant levels in the cell are low and mitochondrial stress increases. (Bottom) Three different treatments can partially or totally rescue inflammatory deficits in Lrrk2 knockout macrophages. First, treating these macrophages with antioxidants alleviates mitochondrial stress and rescues the normal response to interferon. Second, inhibiting DRP1 phosphorylation decreases fission, lowering the level of mitochondrial DNA (green bean-shaped structures) in the cytosol. This prevents the activation of the cGAS/STING pathway, and consequently, the abnormal activation of interferon response genes. Third (and confirming this finding), removing the cGas gene also mitigates increased interferon stimulated gene expression.