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Most cases of AOA are associated with a single dominant mutation in\n                    <jats:italic>OPA1<\/jats:italic>\n                    , which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in\u00a0vivo models of OPA1\u2010mediated AOA, including the first developmentally viable vertebrate\n                    <jats:italic>Opa1<\/jats:italic>\n                    knockout (KO). These models allow for the study of\n                    <jats:italic>Opa1<\/jats:italic>\n                    loss in neurons, specifically RGCs. Though survival is significantly reduced in\n                    <jats:italic>Opa1<\/jats:italic>\n                    deficient zebrafish and\n                    <jats:italic>Drosophila<\/jats:italic>\n                    , both models permit the study of viable larvae. Moreover, zebrafish\n                    <jats:italic>Opa1<\/jats:italic>\n                    KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to\n                    <jats:italic>Opa1<\/jats:italic>\n                    loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting\n                    <jats:italic>Opa1<\/jats:italic>\n                    's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in\n                    <jats:italic>Opa1<\/jats:italic>\n                    deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.\n                  <\/jats:p>","DOI":"10.1096\/fj.202403271r","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T12:22:33Z","timestamp":1744201353000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel in\u00a0vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5490-0894","authenticated-orcid":false,"given":"Elin L.","family":"Strachan","sequence":"first","affiliation":[{"name":"UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin  Dublin Ireland"},{"name":"UCD School of Biomolecular and Biomedical Science University College Dublin  Dublin 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Biomedical Research University College Dublin  Dublin Ireland"},{"name":"UCD School of Medicine University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amandine","family":"Peyrel","sequence":"additional","affiliation":[{"name":"MMDN University of Montpellier, EPHE, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Sarniguet","sequence":"additional","affiliation":[{"name":"MMDN University of Montpellier, EPHE, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Dubois","sequence":"additional","affiliation":[{"name":"MMDN University of Montpellier, EPHE, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2457-6923","authenticated-orcid":false,"given":"Benjamin","family":"Delprat","sequence":"additional","affiliation":[{"name":"MMDN University of Montpellier, EPHE, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7991-4689","authenticated-orcid":false,"given":"Breand\u00e1n N.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin  Dublin Ireland"},{"name":"UCD School of Biomolecular and Biomedical Science University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8244-8145","authenticated-orcid":false,"given":"Niamh C.","family":"O'Sullivan","sequence":"additional","affiliation":[{"name":"UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin  Dublin Ireland"},{"name":"UCD School of Biomolecular and Biomedical Science University College Dublin  Dublin 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