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mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice
Open accessAbstract
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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“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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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Epithelial-Mesenchymal Transitions in Development and Disease
Thiery, J. P., Acloque, H., Huang, R. Y. J., & Nieto, M. A. (2009) · Cell · doi:10.1016/j.cell.2009.11.007 · Cited by 9,931
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., & Greenberg, M. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80405-5 · Cited by 5,689
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088
On Respiratory Impairment in Cancer Cells
Warburg, O. H. (1956) · Science · doi:10.1126/science.124.3215.269 · Cited by 3,472
The Retinal Pigment Epithelium in Visual Function
Strauss, O. (2005) · Physiological Reviews · doi:10.1152/physrev.00021.2004 · Cited by 2,828
Convergence of Wnt, ß-Catenin, and Cadherin Pathways
Nelson, W. J., & Nusse, R. (2004) · Science · doi:10.1126/science.1094291 · Cited by 2,537
Research works printed but not linked: 10
- Exp Eye Res.
- Eagle, 1982, Trans Am Ophthalmol Soc., 80, 218
- Miceli, 1990, Invest Ophthalmol Vis Sci., 31, 277
- Glocklin, 1965, Invest Ophthalmol., 4, 226
- Lacovelli, Invest Ophthalmol Vis Sci.
- Mishima, 1999, Invest Ophthalmol Vis Sci., 40, 1590
- 10.1042/0264-6021:3440427 · DOI
- Liu, 2010, Mol Vis., 16, 184
- Carracedo, 2008, J Clin Invest., 118, 3065
- Kinkade, 2008, J Clin Invest., 118, 3051
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Self-citationAging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,976
Fighting neurodegeneration with rapamycin: mechanistic insights
Bové, J., Martínez‐Vicente, M., & Vila, M. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3068 · Cited by 533
The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422
Kanow, M. A., Giarmarco, M. M., Jankowski, C. S., Tsantilas, K., Engel, A. L., Du, J., Linton, J. D., Farnsworth, C. C., Sloat, S. R., Rountree, A., et al. (2017) · eLife · doi:10.7554/elife.28899 · Cited by 377
Metadata
- 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
- 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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