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Iron, a potent generator of hydroxyl radicals through the Fenton reaction, has been implicated in AMD. One easily oxidized molecule is docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in photoreceptor membranes. Oxidation of DHA produces toxic oxidation products including carboxyethylpyrrole (CEP) adducts, which are increased in the retinas of AMD patients. In this study, we hypothesized that deuterium substitution on the <jats:italic>bis<\/jats:italic>\u2010allylic sites of DHA in photoreceptor membranes could prevent iron\u2010induced retinal degeneration by inhibiting oxidative stress and lipid peroxidation. Mice were fed with either DHA deuterated at the oxidation\u2010prone positions (D\u2010DHA) or control natural DHA and then given an intravitreal injection of iron or control saline. Orally administered D\u2010DHA caused a dose\u2010dependent increase in D\u2010DHA levels in the neural retina and retinal pigment epithelium (RPE) as measured by mass spectrometry. At 1\u00a0week after iron injection, D\u2010DHA provided nearly complete protection against iron\u2010induced retinal autofluorescence and retinal degeneration, as determined by <jats:italic>in vivo<\/jats:italic> imaging, electroretinography, and histology. Iron injection resulted in carboxyethylpyrrole conjugate immunoreactivity in photoreceptors and RPE in mice fed with natural DHA but not D\u2010DHA. Quantitative PCR results were consistent with iron\u2010induced oxidative stress, inflammation, and retinal cell death in mice fed with natural DHA but not D\u2010DHA. Taken together, our findings suggest that DHA oxidation is central to the pathogenesis of iron\u2010induced retinal degeneration. They also provide preclinical evidence that dosing with D\u2010DHA could be a viable therapeutic strategy for retinal diseases involving oxidative stress.<\/jats:p>","DOI":"10.1111\/acel.13579","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T08:55:35Z","timestamp":1646729735000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Deuterated docosahexaenoic acid protects against oxidative stress and geographic atrophy\u2010like retinal degeneration in a mouse model with iron overload"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6652-5358","authenticated-orcid":false,"given":"Yingrui","family":"Liu","sequence":"first","affiliation":[{"name":"F.M. Kirby Center for Molecular Ophthalmology Scheie Eye Institute Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent A.","family":"Bell","sequence":"additional","affiliation":[{"name":"F.M. Kirby Center for Molecular Ophthalmology Scheie Eye Institute Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Song","sequence":"additional","affiliation":[{"name":"F.M. Kirby Center for Molecular Ophthalmology Scheie Eye Institute Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Zhang","sequence":"additional","affiliation":[{"name":"F.M. Kirby Center for Molecular Ophthalmology Scheie Eye Institute Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Anderson","sequence":"additional","affiliation":[{"name":"F.M. Kirby Center for Molecular Ophthalmology Scheie Eye Institute Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul H.","family":"Axelsen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney","family":"Bohannan","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology and Ophthalmology University of Oklahoma Health Sciences Center and the Dean McGee Eye Institute  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin\u2010Paul","family":"Agbaga","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology and Ophthalmology University of Oklahoma Health Sciences Center and the Dean McGee Eye Institute  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui Gyu","family":"Park","sequence":"additional","affiliation":[{"name":"Dell Pediatric Research Institute University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"James","sequence":"additional","affiliation":[{"name":"Dell Pediatric Research Institute University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Thomas","family":"Brenna","sequence":"additional","affiliation":[{"name":"Dell Pediatric Research Institute University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Retrotope, Inc.  Los Altos California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L.","family":"Dunaief","sequence":"additional","affiliation":[{"name":"F.M. Kirby Center for Molecular Ophthalmology Scheie Eye Institute Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail S.","family":"Shchepinov","sequence":"additional","affiliation":[{"name":"Retrotope, Inc.  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