{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:29:19Z","timestamp":1790224159704,"version":"4.1.0"},"reference-count":222,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification.<\/jats:p>","DOI":"10.3390\/biom16030445","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:13:14Z","timestamp":1773659594000},"page":"445","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-1157","authenticated-orcid":false,"given":"Snje\u017eana","family":"Ka\u0161telan","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Clinical Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"Fundamentals of Medical Skills, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9613-8033","authenticated-orcid":false,"given":"Antonela Gverovi\u0107","family":"Antunica","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Dubrovnik General Hospital, 20000 Dubrovnik, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-6790","authenticated-orcid":false,"given":"Suzana","family":"Konjevoda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Zadar General Hospital, 23000 Zadar, Croatia"},{"name":"Department of Health Studies, University of Zadar, 23000 Zadar, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-9254","authenticated-orcid":false,"given":"Zora","family":"Tomi\u0107","sequence":"additional","affiliation":[{"name":"Health Centre of the Croatian, Department of Internal Affairs, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sari\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-8514","authenticated-orcid":false,"given":"Marjan","family":"Kula\u0161","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Zadar General Hospital, 23000 Zadar, Croatia"},{"name":"Postgraduate School, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Kula\u0161","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0702-801X","authenticated-orcid":false,"given":"Emina Kujund\u017ei\u0107","family":"Begovi\u0107","sequence":"additional","affiliation":[{"name":"Eye Clinic, Clinical Center University of Sarajevo, Bolni\u010dka 25, 71000 Sarajevo, Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"\u010canovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Zadar General Hospital, 23000 Zadar, Croatia"},{"name":"Department of Health Studies, University of Zadar, 23000 Zadar, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Kova\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Ivankovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology, Dubrovnik General Hospital, 20000 Dubrovnik, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Marchesi, N., Fahmideh, F., Boschi, F., Pascale, A., and Barbieri, A. 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