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

Area of Science:

• Biochemistry
• Neuroscience
• Ophthalmology

Background:

• Ketone bodies regulate cellular energy and redox balance.
• The role of ketone metabolism in retinal homeostasis is unclear.
• β-hydroxybutyrate dehydrogenase 1 (BDH1) is key for ketone utilization.

Purpose of the Study:

• Investigate the impact of impaired ketone metabolism on retinal function.
• Examine the role of BDH1 in retinal homeostasis.
• Explore ketone metabolism as a therapeutic target for retinal diseases.

Main Methods:

• Generated global and RPE-specific BDH1 knockout mice.
• Performed fundus and OCT imaging, electroretinography (ERG).
• Conducted transcriptomic and molecular analyses; administered exogenous β-hydroxybutyrate.

Main Results:

• Global BDH1 KO mice showed ganglion cell loss and abnormal retinal structure/function.
• RPE-specific BDH1 KO mice had normal retinal morphology and function.
• BDH1 deficiency disrupted Müller cell homeostasis and CAMKII-CREB-EAAT1 signaling.
• Exogenous β-hydroxybutyrate restored signaling, glutamate uptake, and antioxidant gene expression.

Conclusions:

• The BDH1-β-hydroxybutyrate axis is crucial for Müller cell function and retinal integrity.
• Ketone bodies support Müller cell metabolic health, glutamate homeostasis, and redox balance.
• Impaired ketone metabolism is linked to retinal degeneration, suggesting therapeutic potential.