BDH1-Dependent Ketone Body Metabolism Maintains Muller Cell Homeostasis and Retinal Function

Ketone body metabolism serves as an auxiliary regulator of cellular energetics and redox balance, particularly during prolonged fasting and carbohydrate restriction, yet its role in retinal homeostasis under physiological conditions remains poorly defined. {beta}-hydroxybutyrate dehydrogenase 1 (BDH1) is a mitochondrial enzyme that interconverts acetoacetate and {beta}-hydroxybutyrate, and is required for efficient ketone utilization. Here, we investigated the impact of impaired endogenous ketone metabolism on retinal function using global and retinal pigment epithelium (RPE)-specific BDH1 knockout (KO) mice. Global BDH1 KO mice showed reduced circulating {beta}-hydroxybutyrate and blunted fasting-induced ketone elevations, accompanied by ganglion cell loss, structural abnormalities on fundus and OCT imaging, and diminished scotopic and photopic electroretinogram (ERG) a- and b-wave amplitudes, consistent with impaired photoreceptor responses and downstream bipolar and Muller cell signaling. In contrast, RPE-specific BDH1 KO mice exhibited no changes in ERG responses or retinal morphology. Transcriptomic and molecular analyses in global KO retinas revealed disrupted Muller cell homeostasis, including reduced CAMKII-CREB activation, which is required for EAAT1 glutamate transporter expression. Administration of exogenous {beta}-hydroxybutyrate, in vitro and in vivo, restored CAMKII-CREB-EAAT1 signaling, glutamate uptake, and antioxidant gene expression in BDH1 KO mice, demonstrating a central role for ketone bodies in Muller cell metabolic support, glutamate homeostasis, and redox balance. Together with reduced BDH1 expression in human AMD retinas, these findings identify the BDH1-{beta}-hydroxybutyrate axis as a critical metabolic pathway for Muller cell function and retinal integrity, and highlight ketone metabolism as a potential therapeutic target in degenerative retinal diseases.