Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING

Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.