Abstract
Purpose :
Retinal degenerative diseases, such as retinitis pigmentosa (RP), have complex genetic causes but are characterized by the loss of the photoreceptor neurons. For the majority of these diseases, treatment is unavailable. Previously, we found that cellular metabolic pathways were disrupted in the neural retina at RP disease onset in an autosomal recessive (ar) preclinical mouse model, and that replenishing TCA cycle intermediates provided resilience to the photoreceptors against cell death and delayed vision loss in both the arRP and an autosomal dominant (ad) RP preclinical model. Investigation into the duration of photoreceptor resilience and the mechanism underlying the supplementation effect will provide insight into potential treatment targets for patients with RP disease, regardless of the causal genetic mutation.
Methods :
The RhoP23H/+ adRP preclinical mouse model was treated orally with single TCA cycle intermediates (alpha-ketoglutarate, succinate, and citrate) and followed via live imaging and histological analysis through 7 months of age. Additionally, as cells with high metabolic demand and mitochondrial dysfunction have been shown to favor reductive carboxylation to increase lipid metabolism, we profiled hundreds of individual lipids via mass spectrometry analysis from neural retinas of wild-type, arRP, and arRP mice treated with TCA cycle intermediates (alpha-ketoglutarate and citrate).
Results :
We found that replenishment of TCA cycle intermediates in the adRP preclinical mouse model was able to prolong visual function and provide resilience to the photoreceptor neurons against cell death through at least 7 months of age. Furthermore, we detected an altered lipid profile in the neural retinas of mice with RP disease compared to healthy controls, and that supplementation with TCA cycle intermediates restored many of the lipid pathways in the neural retina to levels seen in wild-type controls.
Conclusions :
Enhancement of TCA cycle activity toward altering lipid metabolism provides resilience to the photoreceptor cells against cell death and prolongs visual function in preclinical models of RP, regardless of the causal genetic mutation. Understanding this balance of photoreceptor cell metabolism and its dysregulation during disease can lead to more effective clinical treatments for patients with RP and other forms of retinal degenerative disease.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.