PMID- 23341467 OWN - NLM STAT- MEDLINE DCOM- 20130514 LR - 20231213 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 288 IP - 11 DP - 2013 Mar 15 TI - Autophagy protects the retina from light-induced degeneration. PG - 7506-7518 LID - S0021-9258(19)33535-5 [pii] LID - 10.1074/jbc.M112.439935 [doi] AB - Autophagy is a conserved feature of lysosome-mediated intracellular degradation. Dysregulated autophagy is implicated as a contributor in neurodegenerative diseases; however, the role of autophagy in retinal degeneration remains largely unknown. Here, we report that the photo-activated visual chromophore, all-trans-retinal, modulated autophagosome formation in ARPE19 retinal cells. Increased formation of autophagosomes in these cells was observed when incubated with 2.5 muM all-trans-retinal, a condition that did not cause cell death after 24 h in culture. However, autophagosome formation was decreased at concentrations, which caused cell death. Increased expression of activating transcription factor 4 (Atf4), which indicates the activation of oxidative stress, was recorded in response to light illumination in retinas of Abca4(-/-)Rdh8(-/-) mice, which showed delayed clearance of all-trans-retinal after light exposure. Expression of autophagosome marker LC3B-II and mitochondria-specific autophagy, mitophagy, regulator Park2, were significantly increased in the retinas of Abca4(-/-)Rdh8(-/-) mice after light exposure, suggesting involvement of autophagy and mitophagy in the pathogenesis of light-induced retinal degeneration. Deletion of essential genes required for autophagy, including Beclin1 systemically or Atg7 in only rod photoreceptors resulted in increased susceptibility to light-induced retinal damage. Increased photoreceptor cell death was observed when retinas lacking the rod photoreceptor-specific Atg7 gene were coincubated with 20 muM all-trans-retinal. Park2(-/-) mice also displayed light-induced retinal degeneration. Ultra-structural analyses showed mitochondrial and endoplasmic reticulum impairment in retinas of these model animals after light exposure. Taken together, these observations provide novel evidence implicating an important role of autophagy and mitophagy in protecting the retina from all-trans-retinal- and light-induced degeneration. FAU - Chen, Yu AU - Chen Y AD - Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106; Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China. FAU - Sawada, Osamu AU - Sawada O AD - Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106. FAU - Kohno, Hideo AU - Kohno H AD - Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106. FAU - Le, Yun-Zheng AU - Le YZ AD - Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 43104. FAU - Subauste, Carlos AU - Subauste C AD - Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106. FAU - Maeda, Tadao AU - Maeda T AD - Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106. FAU - Maeda, Akiko AU - Maeda A AD - Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: aam19@case.edu. LA - eng GR - K08 EY019031/EY/NEI NIH HHS/United States GR - P30 EY011373/EY/NEI NIH HHS/United States GR - K08EY019880/EY/NEI NIH HHS/United States GR - R24EY021126/EY/NEI NIH HHS/United States GR - R01EY018341/EY/NEI NIH HHS/United States GR - R01 EY018341/EY/NEI NIH HHS/United States GR - K08EY019031/EY/NEI NIH HHS/United States GR - R01 EY022658/EY/NEI NIH HHS/United States GR - P30EY011373/EY/NEI NIH HHS/United States GR - K08 EY019880/EY/NEI NIH HHS/United States GR - R24 EY021126/EY/NEI NIH HHS/United States GR - R01EY022658/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130122 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (ABCA4 protein, human) RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Abca4 protein, mouse) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Atg7 protein, mouse) RN - 0 (BECN1 protein, human) RN - 0 (Beclin-1) RN - 0 (Becn1 protein, mouse) RN - 0 (Membrane Proteins) RN - 0 (Microtubule-Associated Proteins) RN - 11103-57-4 (Vitamin A) RN - 9009-81-8 (Rhodopsin) RN - EC 1.1.- (Alcohol Oxidoreductases) RN - EC 1.1.1.1 (Alcohol Dehydrogenase) RN - EC 1.1.1.105 (Rdh8 protein, mouse) RN - EC 1.1.1.105 (retinol dehydrogenase) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (parkin protein) RN - EC 6.2.1.45 (ATG7 protein, human) RN - EC 6.2.1.45 (Autophagy-Related Protein 7) RN - EC 6.2.1.45 (Ubiquitin-Activating Enzymes) SB - IM MH - ATP-Binding Cassette Transporters/genetics MH - Alcohol Dehydrogenase/metabolism MH - Alcohol Oxidoreductases/genetics MH - Animals MH - Apoptosis MH - Apoptosis Regulatory Proteins/metabolism MH - Autophagy/*physiology MH - Autophagy-Related Protein 7 MH - Beclin-1 MH - Cell Death MH - Cell Line MH - Humans MH - Light MH - Lysosomes/*metabolism MH - Membrane Proteins/metabolism MH - Mice MH - Mice, Transgenic MH - Microtubule-Associated Proteins/metabolism MH - Photic Stimulation/adverse effects MH - Retina/*metabolism MH - Retinal Degeneration/metabolism MH - Rhodopsin/metabolism MH - Ubiquitin-Activating Enzymes/metabolism MH - Ubiquitin-Protein Ligases/metabolism MH - Vitamin A/metabolism PMC - PMC3597791 EDAT- 2013/01/24 06:00 MHDA- 2013/05/15 06:00 PMCR- 2014/03/15 CRDT- 2013/01/24 06:00 PHST- 2013/01/24 06:00 [entrez] PHST- 2013/01/24 06:00 [pubmed] PHST- 2013/05/15 06:00 [medline] PHST- 2014/03/15 00:00 [pmc-release] AID - S0021-9258(19)33535-5 [pii] AID - M112.439935 [pii] AID - 10.1074/jbc.M112.439935 [doi] PST - ppublish SO - J Biol Chem. 2013 Mar 15;288(11):7506-7518. doi: 10.1074/jbc.M112.439935. Epub 2013 Jan 22.