Nrf2 deficiency decreases NADPH from impaired IDH shuttle and pentose phosphate pathway in retinal pigmented epithelial cells to magnify oxidative stress-induced mitochondrial dysfunction,Aging Cell

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Nrf2 deficiency decreases NADPH from impaired IDH shuttle and pentose phosphate pathway in retinal pigmented epithelial cells to magnify oxidative stress-induced mitochondrial dysfunction
Aging Cell ( IF 8.0 ) Pub Date : 2021-07-27 , DOI: 10.1111/acel.13444
Marisol Cano ₁ , Sayantan Datta ₁ , Lei Wang ₁ , Tongyun Liu ₁ , Miguel Flores-Bellver ₁ , Mira Sachdeva ₁ , Debasish Sinha ₂ , James T Handa ₁

Affiliation

The nuclear factor-erythroid 2-related factor-2 (Nrf2), a major antioxidant transcription factor, is decreased in several age-related diseases including age-related macular degeneration (AMD), the most common cause of blindness among the elderly in western society. Since Nrf2’s mito-protective response is understudied, we investigated its antioxidant response on mitochondria. Control and Nrf2-deficient retinal pigmented epithelial (RPE) cells were compared after treating with cigarette smoke extract (CSE). Mitochondrial antioxidant abundance and reactive oxygen species (ROS) were quantified. Mitochondrial function was assessed by TMRM assay, NADPH, electron transport chain activity, and Seahorse. Results were corroborated in Nrf2^−/− mice and relevance to AMD was provided by immunohistochemistry of human globes. CSE induced mitochondrial ROS to impair mitochondrial function. H₂O₂ increase in particular, was magnified by Nrf2 deficiency, and corresponded with exaggerated mitochondrial dysfunction. While Nrf2 did not affect mitochondrial antioxidant abundance, oxidized PRX3 was magnified by Nrf2 deficiency due to decreased NADPH from decreased expression of IDH2 and pentose phosphate pathway (PPP) genes. With severe CSE stress, intrinsic apoptosis was activated to increase cell death. PPP component TALDO1 immunolabeling was decreased in dysmorphic RPE of human AMD globes. Despite limited regulation of mitochondrial antioxidant expression, Nrf2 influences PPP and IDH shuttle activity that indirectly supplies NADPH for the TRX2 system. These results provide insight into how Nrf2 deficiency impacts the mitochondrial antioxidant response, and its role in AMD pathobiology.

中文翻译：

Nrf2 缺乏会降低视网膜色素上皮细胞中受损的 IDH 穿梭和戊糖磷酸途径产生的 NADPH，从而放大氧化应激诱导的线粒体功能障碍

核因子-红细胞 2 相关因子-2 (Nrf2) 是一种主要的抗氧化转录因子，在多种与年龄相关的疾病中减少，包括年龄相关性黄斑变性 (AMD)，这是西方国家老年人失明的最常见原因社会。由于 Nrf2 的线粒体保护反应尚未得到充分研究，我们研究了它对线粒体的抗氧化反应。在用香烟烟雾提取物 (CSE) 处理后比较对照和 Nrf2 缺陷型视网膜色素上皮 (RPE) 细胞。线粒体抗氧化剂丰度和活性氧 (ROS) 被量化。通过 TMRM 测定、NADPH、电子传递链活性和海马评估线粒体功能。结果在 Nrf2 中得到证实^-/-小鼠和与 AMD 的相关性由人体球体的免疫组织化学提供。CSE 诱导线粒体 ROS 损害线粒体功能。H ₂ O ₂特别是增加，被 Nrf2 缺陷放大，并与夸大的线粒体功能障碍相对应。虽然 Nrf2 不影响线粒体抗氧化剂丰度，但由于 IDH2 和戊糖磷酸途径 (PPP) 基因表达减少导致 NADPH 减少，氧化的 PRX3 被 Nrf2 缺陷放大。在严重的 CSE 应激下，内在细胞凋亡被激活以增加细胞死亡。PPP 组件 TALDO1 免疫标记在人类 AMD 球体的畸形 RPE 中减少。尽管线粒体抗氧化表达的调节有限，但 Nrf2 影响 PPP 和 IDH 穿梭活动，间接为 TRX2 系统提供 NADPH。这些结果提供了对 Nrf2 缺陷如何影响线粒体抗氧化反应及其在 AMD 病理生物学中的作用的深入了解。

更新日期：2021-08-19

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