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Mitochondrial dysfunction plays a central role in this neurodegeneration, yet effective targeted therapies remain limited. Here, we identify the mitochondrial scaffold A-kinase anchoring protein 1 (AKAP1) as a critical regulator of RGC resilience and axon regeneration. AKAP1 expression is diminished in human glaucomatous retinas and experimental glaucoma models, correlating with elevated intraocular pressure, disrupted mitochondrial dynamics, oxidative stress, and synaptic instability. Restoration of AKAP1 via adeno-associated virus serotype 2-mediated gene therapy preserves RGC survival, promotes mitochondrial fusion and cristae integrity, enhances ATP production, and mitigates oxidative and apoptotic stress in mouse models of glaucoma and optic nerve injury. Transcriptomic profiling of AKAP1 knockout retinas reveals widespread dysregulation of mitochondrial and synaptic gene networks. Mechanistically, AKAP1 stabilizes synapses by promoting mitochondrial biogenesis, modulating calcium\/calmodulin-dependent kinase II and synapsin phosphorylation, maintaining synaptophysin expression, and suppressing complement component C1q expression, thereby preventing early synaptic loss in glaucomatous neurodegeneration. Moreover, restoring AKAP1 expression facilitates axonal regeneration, preserves the central visual pathway, and maintains visual function. Collectively, these findings establish AKAP1 as a master regulator of mitochondrial and synaptic homeostasis and axonal regeneration and a promising therapeutic target for vision preservation in glaucomatous neurodegeneration.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>AKAP1 protects retinal ganglion cells and preserves vision by restoring mitochondrial and synaptic health in experimental glaucoma models.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.24.689866","type":"posted-content","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T12:50:11Z","timestamp":1764247811000},"source":"Crossref","is-referenced-by-count":0,"title":["AKAP1 regulates mitochondrial and synaptic homeostasis to enable neuroprotection and repair in retinal ganglion cell degeneration"],"prefix":"10.64898","author":[{"given":"Tonking","family":"Bastola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keun-Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyao","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Perkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muna","family":"Poudel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonjin","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejeong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Yon","family":"Won","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Ho","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark H.","family":"Ellisman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N.","family":"Weinreb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1117-4834","authenticated-orcid":false,"given":"Won-Kyu","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112805050573000_2025.11.24.689866v1.1","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1167\/iovs.17-23277","article-title":"The MT-CO1 V83I Polymorphism is a Risk Factor for Primary Open-Angle Glaucoma in African American Men","volume":"59","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2025112805050573000_2025.11.24.689866v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2022.101136"},{"key":"2025112805050573000_2025.11.24.689866v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2003.10.003"},{"key":"2025112805050573000_2025.11.24.689866v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2006.07.003"},{"key":"2025112805050573000_2025.11.24.689866v1.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140919"},{"key":"2025112805050573000_2025.11.24.689866v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal0092"},{"key":"2025112805050573000_2025.11.24.689866v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3652-17.2018"},{"key":"2025112805050573000_2025.11.24.689866v1.8","doi-asserted-by":"crossref","unstructured":"T. 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