MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium.
AMD
Mtor
aging
lipid
metabolism
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
16
03
2020
revised:
23
06
2020
accepted:
07
07
2020
pubmed:
29
7
2020
medline:
12
3
2021
entrez:
29
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32721041
doi: 10.1096/fj.202000612R
pmc: PMC7811279
mid: NIHMS1660760
doi:
Substances chimiques
Fatty Acids
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12502-12520Subventions
Organisme : NEI NIH HHS
ID : R01 EY028773
Pays : United States
Organisme : NIH HHS
ID : R01-026545
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY025218
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES023485
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY026999
Pays : United States
Organisme : NIH HHS
ID : S10 OD018006
Pays : United States
Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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