Abstract
Purpose :
The mitochondrial pyruvate metabolism is essential in providing energy to cells. Cone photoreceptors are known to consume a large amount of ATP and are shown to be active in mitochondrial pyruvate metabolism. This metabolism pathway is primarily regulated by the pyruvate dehydrogenase (PDH) complex, and can be compensated by increased β-oxidation of fatty acids. Previous studies have shown that this pathway is likely impaired in degenerating cones, manifested as reduced PDH activity, which may accelerate the degeneration further. This work investigates whether mitochondrial pyruvate metabolism is impaired in retinas of cone degeneration mouse models and whether supplementation of a ketogenic diet to increase β-oxidation of fatty acids can compensate for metabolic activity and reduce cone degeneration.
Methods :
Cnga3-/- mice (a model of achromatopsia), Rpe65-/- mice (a model of Leber congenital amaurosis), Cnga3-/-Nrl-/- mice (on a cone-dominant background), and Rpe65-/-Nrl-/- mice were used. The activity of PDH was evaluated by analyzing the phospho-PDH levels using immunoblotting. Ketogenic diet or control diet was administered to mice for various lengths of time (between 10 days and 3 months). Cone density was analyzed via labeling of peanut agglutinin on retinal whole mounts and cone death was evaluated via terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) on retinal cross-sections.
Results :
The protein expression levels of phospho-PDH were significantly increased in retinas of Cnga3-/-Nrl-/- mice and Rpe65-/-Nrl-/- mice. Cnga3-/- mice and Rpe65-/- mice that were fed with a ketogenic diet showed an increased cone density, compared to mice fed with standard diet or keto-control diet. Cnga3-/-Nrl-/- mice that were given a ketogenic diet had a significant reduction in the number of TUNEL-positive cells, compared to controls.
Conclusions :
Data from this work suggest a potential defect of mitochondrial pyruvate metabolism in degenerating cones and that ketogenic diet to compensate for the metabolism defect may be beneficial for cone protection in retinal degeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.