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Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa
Yogita Kanan1, Sean F Hackett1, Kamil Taneja1
1The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract:
Retinitis pigmentosa occurs due to mutations that cause rod photoreceptor degeneration. Once most rods are lost, gradual degeneration of cone photoreceptors occurs. Oxidative damage and abnormal glucose metabolism have been implicated as contributors to cone photoreceptor death. Herein, we show increased phosphorylation of key enzymes of glucose metabolism in the retinas of rd10 mice, a model of RP, and retinas of wild type mice with paraquat-induced oxidative stress, thereby inhibiting these key enzymes. Dietary supplementation with glucose and pyruvate failed to overcome the inhibition, but increased reducing equivalents in the retina and improved cone function and survival. Dichloroacetate reversed the increased phosphorylation of pyruvate dehydrogenase in rd10 retina and increased histone acetylation and levels of TP53-induced glycolysis and apoptosis regulator (TIGAR), which redirected glucose metabolism toward the pentose phosphate pathway. These data indicate that oxidative stress induced damage can be reversed by shifting glycolytic intermediates toward the pentose phosphate pathway which increases reducing equivalents and provides photoreceptor protection.
Insights
Oxidative stress damages cone photoreceptors in retinitis pigmentosa (RP). Shifting glucose metabolism to the pentose phosphate pathway protects cones by increasing reducing equivalents.
Area of Science:
- Ophthalmology
- Neuroscience
- Metabolic pathways
Background:
- Retinitis pigmentosa (RP) involves rod photoreceptor degeneration, leading to secondary cone photoreceptor loss.
- Oxidative damage and altered glucose metabolism are implicated in cone cell death during RP progression.
Purpose of the Study:
- To investigate the role of glucose metabolism and oxidative stress in cone degeneration in RP.
- To explore therapeutic strategies targeting metabolic pathways for photoreceptor protection.
Main Methods:
- Analysis of key glucose metabolism enzymes in rd10 mouse retinas (RP model) and paraquat-induced oxidative stress models.
- Assessment of dietary supplementation (glucose, pyruvate) and dichloroacetate (DCA) effects on retinal metabolism and cone function.
- Measurement of phosphorylation, histone acetylation, and TIGAR (TP53-induced glycolysis and apoptosis regulator) levels.
Main Results:
- Increased phosphorylation and inhibition of key glucose metabolism enzymes were observed in RP and oxidative stress models.
- Dietary interventions failed to restore function, but increased reducing equivalents, improving cone survival.
- Dichloroacetate reversed pyruvate dehydrogenase phosphorylation, increased histone acetylation and TIGAR, redirecting metabolism to the pentose phosphate pathway.
Conclusions:
- Oxidative stress-induced damage in RP retinas involves inhibition of glucose metabolism enzymes.
- Shifting glycolytic intermediates toward the pentose phosphate pathway enhances reducing equivalents and protects cone photoreceptors.
- Targeting metabolic pathways, like with dichloroacetate, offers a potential therapeutic strategy for RP.
