Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa

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.

Automated summary

Retinitis pigmentosa is caused by mutations leading to degeneration of rod photoreceptors, followed by gradual degeneration of cone photoreceptors. Oxidative damage and abnormal glucose metabolism are implicated in cone photoreceptor death. This study shows that shifting glycolytic intermediates towards the pentose phosphate pathway can reverse oxidative stress-induced damage, increase reducing equivalents, and provide photoreceptor protection.