mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice
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Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress.
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Sustained mTOR activation in the RPE via chemical or genetic approaches causes metabolic reprogramming, dedifferentiation, and hypertrophy of the RPE.
“This is illustrated by studies in mouse models showing that sustained mTOR activation in the RPE via chemical or genetic approaches causes metabolic reprogramming, dedifferentiation, and hypertrophy of the RPE”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Zhao et al., 2011
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Yang, X., Chung, J., Rai, U., & Esumi, N. (2018) · PLoS ONE · doi:10.1371/journal.pone.0191279 · Cited by 50 · see citing works
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MTOR‐initiated metabolic switch and degeneration in the retinal pigment epithelium
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- Authors
- Zhao, C., Yasumura, D., Li, X., Matthes, M., Lloyd, M., Nielsen, G., Ahern, K., Snyder, M., Bok, D., Dunaief, J. L., LaVail, M. M., & Vollrath, D.
- Affiliations
- Stanford Medicine (US)
- University of California, San Francisco (US)
- University of California, Los Angeles (US)
- University of Pennsylvania (US)
- Corresponding author
- Vollrath, Douglas
- Venue
- Journal of Clinical Investigation
- Published
- 2011-01-04
- Volume
- 121
- Issue
- 1
- Pages
- 369-383
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3007156
- OpenAlex
- W2002712265
- Cited by
- 303
- References
- 89
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 25 · 2023: 27 · 2022: 31 · 2021: 26 · 2020: 35 · 2019: 16 · 2018: 11 · 2017: 20 · 2016: 16 · 2015: 18 · 2014: 23 · 2013: 15 · 2012: 10
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness (EY00331, P30EY002162)
- Edward N. and Della L. Thome Memorial Foundation
- National Institutes of Health (EY 00331, EY001919)
- National Eye Institute (EY 015240, P30EY002162, R01EY001919, EY-00331, R03EY014650, R01EY006842, EY001919, R01EY015240, P30EY000331, EY014650)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- retinal pigment epithelium, photoreceptor degeneration, mTOR signaling, Akt/mTOR signaling, glycolysis, hepatocyte growth factor, MET oncogene, rapamycin, retinal degeneration
- MeSH terms
- Animals, Autophagy, Cell Movement, Cell Survival, Female, Glycolysis, Hypertrophy, Male, Mice, Transgenic, Oxidative Phosphorylation, Retinal Degeneration, Signal Transduction, Cell Death, Hepatocyte Growth Factor, Proto-Oncogene Proteins c-met, Sirolimus, Photoreceptor Cells, Vertebrate, Proto-Oncogene Proteins c-akt, Mice, Cell Dedifferentiation, Retinal Pigment Epithelium, TOR Serine-Threonine Kinases
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