Publication Date
9-1-2020
Journal
The FASEB Journal
DOI
10.1096/fj.202000612R
PMID
32721041
PMCID
PMC7811279
PubMedCentral® Posted Date
1-16-2021
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Aging, Animals, Disease Models, Animal, Fatty Acids, Glucose, Macular Degeneration, Mechanistic Target of Rapamycin Complex 1, Metabolome, Mice, Mice, Inbred C57BL, Mice, Knockout, Retinal Pigment Epithelium, Transcriptome
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.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Endocrinology, Diabetes, and Metabolism Commons, Eye Diseases Commons, Medical Immunology Commons, Ophthalmology Commons, Optometry Commons
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