The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Free Radic Biol Med. 2022 Mar;181:143-153. doi: 10.1016/j.freeradbiomed.2022.01.032. Epub 2022 Feb 5.
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.
色素性视网膜炎是由于导致视杆细胞变性的突变引起的。一旦大多数视杆细胞丢失，视锥细胞就会逐渐退化。氧化损伤和异常的葡萄糖代谢被认为是导致视锥细胞死亡的因素。在此，我们发现在 rd10 小鼠模型（一种 RP 模型）和百草枯诱导的氧化应激的野生型小鼠的视网膜中，葡萄糖代谢的关键酶的磷酸化增加，从而抑制这些关键酶。用葡萄糖和丙酮酸进行饮食补充未能克服这种抑制作用，但增加了视网膜中的还原当量，并改善了视锥细胞的功能和存活。二氯乙酸逆转了 rd10 视网膜中丙酮酸脱氢酶的过度磷酸化，并增加了组蛋白乙酰化和 TP53 诱导的糖酵解和凋亡调节剂（TIGAR）的水平，这将葡萄糖代谢重定向到戊糖磷酸途径。这些数据表明，通过将糖酵解中间产物转移到戊糖磷酸途径，可以逆转氧化应激引起的损伤，从而增加还原当量并提供光感受器保护。
