{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:12:18Z","timestamp":1788786738794,"version":"build-2803163510"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Age-related macular degeneration (AMD) is the leading cause of blindness in aging adults, yet no FDA-approved therapies exist for early and intermediate disease. Multiple interconnected pathways, including mitochondrial dysfunction, oxidative stress, and inflammation, contribute to retinal pigment epithelium (RPE) degeneration in AMD, highlighting the need for developing new cytoprotective strategies. The MTRNR2L gene family, comprising nuclear paralogs of mitochondrial-derived peptide humanin, has emerged as a potential regulator of these pathways. Humanin has demonstrated anti-apoptotic, anti-inflammatory, and mitochondrial-stabilizing effects across multiple cell types, including the RPE. Recent transcriptomic and single-cell RNA-sequencing (scRNA-seq) analyses indicate that MTRNR2L genes are upregulated in a variety of human diseases associated with cellular stress response, inflammation, angiogenesis, and neurodegeneration. These findings suggest that MTRNR2L genes participate in coordinated stress-adaptive programs and may mirror humanin\u2019s cytoprotective and immunomodulating actions. This review summarizes recent research advances and highlights key gaps for understanding the roles of the MTRNR2L family in RPE protection and AMD progression.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1925795","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:56:40Z","timestamp":1788785800000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The MTRNR2L gene family and age-related macular degeneration"],"prefix":"10.3389","volume":"17","author":[{"given":"Adam","family":"Moosa","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York","place":["Buffalo, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York","place":["Buffalo, NY, United States"]},{"name":"Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York","place":["Buffalo, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M.","family":"DeAngelis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York","place":["Buffalo, NY, United States"]},{"name":"Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York","place":["Buffalo, NY, United States"]},{"name":"Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New 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