Cited by 303Retinal Development and DisordersRetinal Diseases and TreatmentsAutophagy in Disease and Therapy

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mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

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Zhao, Chen, Yasumura, Douglas, Li, Xiyan, Matthes, Michael, Lloyd, Marcia, Nielsen, Gregory, Ahern, Kelly, Snyder, Michael, Bok, Dean, Dunaief, Joshua L., LaVail, Matthew M., Vollrath, Douglas·2011·Journal of Clinical Investigation

DOI 10.1172/jci44303PMC PMC3007156

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Abstract

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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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
ORCID: Zhao, Chen
Li, Xiyan
Matthes, Michael
Snyder, Michael
Dunaief, Joshua L.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2011-01-04
Volume: 121
Issue: 1
Pages: 369-383
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci44303
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: Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

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