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MTOR‐initiated metabolic switch and degeneration in the retinal pigment epithelium
The FASEB Journal ( IF 4.4 ) Pub Date : 2020-07-28 , DOI: 10.1096/fj.202000612r
Young-Mi Go 1 , Jing Zhang 2 , Jolyn Fernandes 1, 3 , Christopher Litwin 4 , Rui Chen 5, 6 , Theodore G Wensel 6 , Dean P Jones 1 , Jiyang Cai 2, 7 , Yan Chen 2, 4, 8
Affiliation  

The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age‐dependent degeneration. Over the life span, the RPE develops an expanded endo‐lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high‐resolution metabolomic and genomic approaches to examine mice with RPE‐specific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC1. Our data show that RPE cells with constitutively high mTORC1 activity were reprogramed to be hyperactive in glucose and lipid metabolism. Lipolysis was suppressed, mitochondrial carnitine shuttle was inhibited, while genes involved in fatty acid (FA) biosynthesis were upregulated. The metabolic changes occurred prior to structural changes of RPE and retinal degeneration. These findings have revealed cellular events and intrinsic mechanisms that contribute to lipid accumulation in the RPE cells during aging and age‐related degeneration.

中文翻译:

MTOR 引发的视网膜色素上皮代谢转换和变性

视网膜色素上皮 (RPE) 是一种特别容易发生年龄依赖性变性的组织。在整个生命周期中,RPE 会形成一个扩大的内溶酶体区室,以保持光感受器存活所必需的光感受器外段 (POS) 吞噬和降解的高效率。由于雷帕霉素复合物 1 (mTORC1) 的机械目标的组装和激活发生在溶酶体表面,随着年龄的增长溶酶体质量增加导致更高的 mTORC1 活性。RPE 中过度活跃的 mTORC1 的功能后果尚不清楚。在当前的研究中,我们使用集成的高分辨率代谢组学和基因组方法来检查具有 RPE 特异性缺失结节性硬化症 1 (Tsc1) 基因的小鼠,该基因编码 mTORC1 的上游抑制因子。我们的数据显示,具有组成性高 mTORC1 活性的 RPE 细胞被重新编程为在葡萄糖和脂质代谢中过度活跃。脂肪分解被抑制,线粒体肉碱穿梭被抑制,而参与脂肪酸 (FA) 生物合成的基因被上调。代谢变化发生在 RPE 和视网膜变性的结构变化之前。这些发现揭示了在衰老和与年龄相关的退化过程中导致 RPE 细胞中脂质积累的细胞事件和内在机制。
更新日期:2020-07-28
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