# Loss of Kv8.2 in the Mouse Retina Is Associated With Altered One‐Carbon Metabolism

## TL;DR

This study shows that a genetic mutation in mice leads to changes in retinal metabolism, particularly in one-carbon metabolism, which may contribute to slow retinal degeneration.

## Contribution

The study identifies altered one-carbon metabolism as a novel mechanism in retinal degeneration caused by impaired photoreceptor ion homeostasis.

## Key findings

- Aged Kv8.2 knockout retinas show elevated levels of one-carbon metabolites like serine, methionine, and homocysteine.
- Nucleobases and nucleosides are reduced in aged Kv8.2 knockout retinas compared to wildtype.
- Metabolic changes in one-carbon metabolism emerge early and progress with age in Kv8.2 knockout retinas.

## Abstract

Photoreceptors are highly energy‐demanding neurons, and disruption of photoreceptor signaling remodels retinal metabolism and contributes to degeneration, yet the pathways underlying these changes remain incompletely defined. Kv8.2 knockout (KO) mice, a model of KCNV2 retinopathy, exhibit impaired photoreceptor ion homeostasis and slow rod degeneration, providing an opportunity to investigate metabolic adaptation during progressive dysfunction. Untargeted metabolomic profiling was performed on retinas from wildtype (WT) and Kv8.2 KO mice at 1 and 13 months of age. Principal component analysis revealed distinct profiles for aged Kv8.2 KO retinas compared with aged WT and young groups, while young WT and KO retinas were metabolically similar. The major changes in aged Kv8.2 KO retinas compared to aged WT were reduced nucleobases and nucleosides while the amino acids homocysteine, methionine, and serine were elevated. These are signature metabolites in one‐carbon metabolism, a metabolic hub influencing nucleotide metabolism, epigenic regulation, and anti‐oxidant defense. Supervised modeling showed that these one‐carbon–related changes emerge early and progress with age in Kv8.2 KO retinas. Together, these findings implicate altered one‐carbon metabolism as a key mechanism in photoreceptor vulnerability and adaptation in slow retinal degeneration.

Kv8.2 knockout mice, a model of KCNV2 retinopathy, exhibit impaired potassium homeostasis in photoreceptors and slowly progressive rod degeneration. To investigate metabolic adaptations accompanying this dysfunction, untargeted metabolomic profiling was performed on mouse retinas. The analysis revealed age‐dependent remodeling of retinal metabolism in Kv8.2 knockout mice. Metabolites associated with one‐carbon metabolism, including serine, methionine, and homocysteine, were increased, while nucleotide metabolites derived from purine and pyrimidine synthesis were reduced. These findings indicate that disruption of photoreceptor ion homeostasis is accompanied by reorganization of the one‐carbon metabolic network, linking metabolic adaptation to progressive retinal degeneration.