MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium.
MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium.
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DOI：
10.1096/fj.202000612r
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Go YM;Zhang J;Fernandes J;Litwin C;Chen R;Wensel TG;Jones DP;Cai J;Chen Y
视网膜色素上皮（RPE）是一种对年龄相关性退变特别敏感的组织。在整个生命周期中，RPE会形成一个扩大的内溶酶体区室，以维持光感受器外节（POS）吞噬和降解的高效率，这对光感受器的存活是必需的。由于雷帕霉素复合物1（mTORC1）的机制靶点的组装和激活发生在溶酶体表面，随着年龄增长溶酶体数量增加导致mTORC1活性升高。RPE中mTORC1过度活跃的功能后果尚不清楚。在当前的研究中，我们使用综合的高分辨率代谢组学和基因组学方法来研究视网膜色素上皮特异性缺失结节性硬化症1（Tsc1）基因的小鼠，该基因编码mTORC1的一种上游抑制因子。我们的数据显示，具有持续高mTORC1活性的RPE细胞在葡萄糖和脂质代谢方面被重新编程为过度活跃。脂解作用受到抑制，线粒体肉碱穿梭被抑制，而参与脂肪酸（FA）生物合成的基因上调。这些代谢变化发生在RPE结构变化和视网膜退变之前。这些发现揭示了在衰老和年龄相关性退变过程中导致RPE细胞中脂质积累的细胞事件和内在机制。
The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the lifespan, 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.