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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,16]]},"abstract":"<jats:p>\n                    Age-related macular degeneration, Stargardt disease, and their\n                    <jats:italic>\n                      Abca4\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2022\u2013<\/jats:sup>\n                    ) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2022\u2013<\/jats:sup>\n                    or nitric oxide (\n                    <jats:sup>\u2022<\/jats:sup>\n                    NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2022\u2013<\/jats:sup>\n                    plus\n                    <jats:sup>\u2022<\/jats:sup>\n                    NO creates a dioxetane on melanin that excites its electrons\u00a0to a high-energy state (termed \u201cchemiexcitation\u201d), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2216935120","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T15:17:50Z","timestamp":1683559070000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":14,"title":["Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6928-5994","authenticated-orcid":false,"given":"Yanan","family":"Lyu","sequence":"first","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5112-8838","authenticated-orcid":false,"given":"Alexander V.","family":"Tschulakow","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen 72076, Germany"},{"name":"OcuTox GmbH, Preclinical Drug Assessment, Hechingen 72379, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-8651","authenticated-orcid":false,"given":"Kun","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7437-9373","authenticated-orcid":false,"given":"Douglas E.","family":"Brash","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040"},{"name":"Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8028"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7969-8426","authenticated-orcid":false,"given":"Ulrich","family":"Schraermeyer","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen 72076, Germany"},{"name":"OcuTox GmbH, Preclinical Drug Assessment, Hechingen 72379, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-007-9118-6"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/364396a0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.315432"},{"key":"e_1_3_4_4_2","article-title":"Bisretinoids of the retina: Photo-oxidation, iron-catalyzed oxidation, and disease consequences","volume":"10","author":"Kim H. J.","year":"2021","unstructured":"H. J. Kim, D. Montenegro, J. Zhao, J. R. Sparrow, Bisretinoids of the retina: Photo-oxidation, iron-catalyzed oxidation, and disease consequences. Antioxidants (Basel) 10 (2021).","journal-title":"Antioxidants (Basel)"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.TR120000742"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-11688"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.5215"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.09.048"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901784RR"},{"key":"e_1_3_4_10_2","first-page":"195","article-title":"Aging human RPE: Morphometric analysis of macular, equatorial, and peripheral cells","volume":"25","author":"Feeney-Burns L.","year":"1984","unstructured":"L. Feeney-Burns, E. S. Hilderbrand, S. 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