Department of Medicine, Emory University, Atlanta, GA, USA.
Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX, USA.
FASEB J. 2020 Sep;34(9):12502-12520. doi: 10.1096/fj.202000612R. Epub 2020 Jul 28.
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.
视网膜色素上皮（RPE）是一种特别容易受到年龄相关退化影响的组织。在整个生命周期中，RPE 会发展出一个扩大的内溶酶体隔室，以维持对光感受器外节（POS）的高效吞噬和降解，这对于光感受器的存活是必要的。由于雷帕霉素靶蛋白复合物 1（mTORC1）的组装和激活发生在溶酶体表面，因此随着年龄的增长，溶酶体质量的增加会导致更高的 mTORC1 活性。RPE 中过度活跃的 mTORC1 的功能后果尚不清楚。在本研究中，我们使用整合的高分辨率代谢组学和基因组学方法，研究了 RPE 特异性缺失编码 mTORC1 上游抑制剂的结节性硬化症 1（Tsc1）基因的小鼠。我们的数据表明，RPE 细胞中持续高 mTORC1 活性被重新编程为在葡萄糖和脂质代谢中过度活跃。脂解被抑制，线粒体肉碱穿梭被抑制，而参与脂肪酸（FA）合成的基因被上调。这些代谢变化发生在 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。
