Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa.
Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa.
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DOI：
10.1016/j.freeradbiomed.2022.01.032
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发表时间：
2022-03
影响因子：
7.4
通讯作者：
Campochiaro PA
中科院分区：
文献类型：
--
作者：
Kanan Y;Hackett SF;Taneja K;Khan M;Campochiaro PA
视网膜色素变性的发生是由于突变导致视杆细胞变性。一旦大多数视杆细胞丢失，锥状光感受器就会逐渐退化。氧化损伤和葡萄糖代谢异常被认为是视锥细胞死亡的原因。在此，我们发现增加磷酸化的葡萄糖代谢的关键酶在视网膜的rd10小鼠，RP模型，和视网膜的野生型小鼠百草枯诱导的氧化应激，从而抑制这些关键酶。饮食中补充葡萄糖和丙酮酸未能克服抑制，但增加了视网膜中的还原当量，改善了视锥细胞的功能和存活率。二氯乙酸逆转了rd10视网膜中丙酮酸脱氢酶磷酸化的增加，并增加了组蛋白乙酰化和TP 53诱导的糖酵解和凋亡调节因子（TIGAR）的水平，从而将葡萄糖代谢重定向到磷酸戊糖途径。这些数据表明，氧化应激诱导的损伤可以通过将糖酵解中间体转移到戊糖磷酸途径来逆转，这增加了还原当量并提供了感光细胞保护。
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.
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