Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.

Mitochondria are central regulators of retinal bioenergetics and innate immune signaling, yet how mitochondrial genetic background and aging jointly influence immunometabolic responses in the retina remains poorly defined. Here, we investigated the effects of mitochondrial DNA (mtDNA) variation on retinal function and the combined effects of mtDNA variation and age on bioenergetic composition, mtDNA damage, and the microglial expression and intracellular localization of stimulator of interferon genes (STING) protein. Using mitochondrial-nuclear eXchange (MNX) mice harboring identical C57BL/6J nuclear genomes but distinct C57 or C3H mtDNA haplotypes, we assessed oxidative phosphorylation complex composition, electrophysiological function, mtDNA damage, and microglial STING dynamics across the lifespan and following acute intraocular pressure (IOP) elevation. Aging was associated with increased mtDNA damage and remodeling of oxidative phosphorylation complex composition, characterized by reduced Complex III and V abundance and increased Complex IV. Despite these age-associated changes, photoreceptor- and retinal ganglion cell-associated retinal responses were preserved at early ages, whereas bipolar cell-associated responses differed by mtDNA background. Microglial STING expression increased with age. Acute IOP elevation was associated with differential microglial STING dynamics and STING association with lysosomal compartments decreased with age. Together, these findings demonstrate that mitochondrial genetic background and aging influence retinal bioenergetics and neuroimmune protein expression and identify mtDNA variation as a modifier of age-associated microglial STING expression in the retina.