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A high\u2010fat diet (HFD) can lead to lipid metabolism disorders, excessive production of circulating free fatty acids, and systemic inflammation by aggravating the degree of oxidative stress. Deletion of the retinal G\u2010protein\u2010coupled receptor (RGR\u2010d) has been identified in drusen. In this study, we investigated how the RGR\u2010d exacerbates AMD\u2010like changes under oxidative stress, both in\u00a0vivo and in\u00a0vitro. Fundus atrophy became evident, at 12\u2009months old, particularly in the RGR\u2010d\u2009+\u2009HFD group, and fluorescence angiography revealed narrower retinal vessels and a reduced perfusion area in the peripheral retina. Although rod electroretinography revealed decreasing trends in the a\u2010 and b\u2010wave amplitudes in the RGR\u2010d\u2009+\u2009HFD group at 12\u2009months, the changes were not statistically significant. Mice in the RGR\u2010d\u2009+\u2009HFD group showed a significantly thinner and more fragile retinal morphology than those in the WT\u2009+\u2009HFD group, with disordered and discontinuous pigment distribution in the RGR\u2010d\u2009+\u2009HFD mice. Transmission electron microscopy revealed a thickened Bruch's membrane along the choriocapillaris endothelial cell wall in the RGR\u2010d\u2009+\u2009HFD mice, and the outer nuclear layer structure appeared disorganized, with reduced nuclear density. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significantly lower levels of 25(OH)\u2010vitamin D3 metabolites in the RGR\u2010d\u2009+\u2009HFD group. Under oxidative stress, RGR\u2010d localized to the mitochondria and reduced the levels of the PINK1\u2013parkin pathway. RGR\u2010d mice fed an HFD were used as a new animal model of dry AMD. Under high\u2010fat\u2010induced oxidative stress, RGR\u2010d accumulated in the mitochondria, disrupting normal mitophagy and causing cellular damage, thus exacerbating AMD\u2010like changes both in\u00a0vivo and in\u00a0vitro.<\/jats:p>","DOI":"10.1096\/fj.202401160rr","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T14:50:38Z","timestamp":1730127038000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Retinal G\u2010protein\u2010coupled receptor deletion exacerbates\n                    <scp>AMD<\/scp>\n                    \u2010like changes via the\n                    <scp>PINK1<\/scp>\n                    \u2013parkin pathway under oxidative stress"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4191-3183","authenticated-orcid":false,"given":"Yue","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5159-7957","authenticated-orcid":false,"given":"Sitong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8412-8479","authenticated-orcid":false,"given":"Wenxue","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-5422","authenticated-orcid":false,"given":"Ningda","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9051-6603","authenticated-orcid":false,"given":"Li","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7953-2023","authenticated-orcid":false,"given":"Wei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Peking University People's Hospital  Beijing China"},{"name":"Eye Diseases and Optometry Institute  Beijing China"},{"name":"Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases  Beijing China"},{"name":"College of Optometry Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9934-5808","authenticated-orcid":false,"given":"Henry K. 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