MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium

• Type of Material: Article
• Authors: Young-Mi Go, Emory University; Jing Zhang, University of Texas Medical Branch; Jolyn Fernandes, Emory University; Christopher Litwin, University of Oklahoma Health Sciences Center; Rui Chen, Baylor College of Medicine; Theodore G. Wensel, Baylor College of Medicine; Dean Jones, Emory University; Jiyang Cai, University of Texas Medical Branch; Yan Chen, University of Texas Medical Branch
• Language: English
• Date: 2020-07-28
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1096/fj.202000612R
• Title of Journal or Parent Work: FASEB JOURNAL
• Volume: 34
• Issue: 9
• Start Page: 12502
• End Page: 12520
• Grant/Funding Information: This work was supported by NIH grants R01EY026999 (YC), R01EY 028773 (JC), R01EY025218 (TGW), R01-026545 (TGW), NIEHS grants R01ES023485 (DPJ and YMG) and NIHS10 OD018006 (DPJ), BrightFoucs Foundation grant M2017186 (YC), and Welch Foundation Q0035 (TGW). The authors will like to acknowledge the Oklahoma University Health Science Center (OUHSC) Vision Research Facilities for the Live Animal Imaging Core, Genotyping Core and Cellular Imaging Core services. The cores are supported by NIH/NEI grant P30EY027125 to Dr. Michelle C. Callegan and an unrestricted grant from Research to Prevent Blindness to the Dean McGee Eye Institute. We also will like to thank the Molecular Biology and Cytometry Research Shared Resource at OUHSC which provided the Metabolic Analysis of Live Cells service.
• Keywords: GROWTH; Cell Biology; MOUSE MODEL; AMD; RAPAMYCIN; MECHANISTIC TARGET; Biochemistry & Molecular Biology; Science & Technology; FATTY-ACIDS; CELLS; GEOGRAPHIC ATROPHY; lipid; Life Sciences & Biomedicine - Other Topics; MACULAR DEGENERATION; aging; Life Sciences & Biomedicine; metabolism; Biology; LIFE-SPAN; DOCOSAHEXAENOIC ACID; Mtor
• Research Categories: Biology, Cell; Chemistry, Biochemistry; Biology, Molecular

Abstract

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.