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Published on: January 12, 2022
Loss of Kv8.2 in the Mouse Retina Is Associated With Altered One-Carbon Metabolism
Karina Kruth1, Sheila A Baker1,2
1Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa, Iowa, USA.
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.
Insights
Altered one-carbon metabolism is key in slow retinal degeneration. This study in Kv8.2 knockout mice reveals metabolic shifts impacting photoreceptor function and survival.
Area of Science:
- Neuroscience
- Metabolomics
- Ophthalmology
Background:
- Photoreceptors are energy-intensive neurons; their signaling disruption alters retinal metabolism and causes degeneration.
- The specific metabolic pathways involved in photoreceptor dysfunction and degeneration are not fully understood.
Purpose of the Study:
- To investigate metabolic adaptations in photoreceptors during progressive degeneration using Kv8.2 knockout (KO) mice, a model for KCNV2 retinopathy.
- To identify key metabolic pathways altered in aging retinas with impaired photoreceptor function.
Main Methods:
- Untargeted metabolomic profiling of retinas from wildtype (WT) and Kv8.2 KO mice at young (1 month) and aged (13 months) stages.
- Principal component analysis (PCA) and supervised modeling to compare metabolic profiles between groups and identify age-related changes.
Main Results:
- Aged Kv8.2 KO retinas showed distinct metabolic profiles compared to aged WT and young mice.
- Key alterations in aged Kv8.2 KO retinas included reduced nucleobases/nucleosides and elevated homocysteine, methionine, and serine.
- These changes are characteristic of one-carbon metabolism, a critical hub for nucleotide synthesis, epigenetics, and antioxidant defense.
Conclusions:
- Altered one-carbon metabolism emerges early and progresses with age in Kv8.2 KO retinas.
- This metabolic shift is implicated as a significant mechanism underlying photoreceptor vulnerability and adaptation in slow retinal degeneration.
