Mitochondrial mechanism in retinal astrocytes underlies neovascular retinopathy.

Mitochondrial diseases often manifest as different forms of retinopathy and mitochondrial roles are also suggested in common forms of irreversible blindness such as diabetic retinopathy. To explore the glial contributions in retinal homeostasis, we inactivated the mitochondrial DNA helicase Twinkle in astrocytes (TwKOAstro). The TwKOAstro reactivates retinal astrocytes leading to neovascular growth, blood-retina-barrier leakage, and complement cascade activation. Spike recordings on the most sensitive ON and OFF sustained alpha ganglion cells of retina showed no difference in their light sensitivity at visual threshold as compared to wild type mice indicating normal rod function and retinal coding. While cerebral cortex in TwKOAstro mice showed astrocyte reactivation, the vascular barriers were intact and neovascular growth absent, pointing to unique vulnerability of retina to mitochondrial dysregulation. Our findings unveil an essential role of glial mitochondria in neovascular retinopathy, with important implications for therapy development for mitochondrial and common forms of vision loss