{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:50:32Z","timestamp":1792803032248,"version":"4.5.0"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY031697"],"award-info":[{"award-number":["EY031697"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY034116"],"award-info":[{"award-number":["EY034116"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY022589"],"award-info":[{"award-number":["EY022589"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research to Prevent Blindness (New York, NY, USA)","award":["EY031697"],"award-info":[{"award-number":["EY031697"]}],"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Research to Prevent Blindness (New York, NY, USA)","award":["EY034116"],"award-info":[{"award-number":["EY034116"]}],"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Research to Prevent Blindness (New York, NY, USA)","award":["EY022589"],"award-info":[{"award-number":["EY022589"]}],"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)\/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is a key regulator of the cyclic adenosine monophosphate (cAMP)\/protein kinase A (PKA) signaling pathway, which is known to protect mitochondria and promote RGC survival. However, the precise molecular mechanisms connecting the sAC-mediated signaling pathway with mitochondrial protection in RGCs against oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress induced by ischemic injury and paraquat administration, we found that administration of bicarbonate, as an activator of sAC, protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death. Notably, the administration of bicarbonate ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.<\/jats:p>","DOI":"10.3390\/antiox13060743","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T05:27:19Z","timestamp":1718861239000},"page":"743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Administration of Bicarbonate Protects Mitochondria, Rescues Retinal Ganglion Cells, and Ameliorates Visual Dysfunction Caused by Oxidative Stress"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3779-7178","authenticated-orcid":false,"given":"Tonking","family":"Bastola","sequence":"first","affiliation":[{"name":"Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Perkins","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viet Anh Nguyen","family":"Huu","sequence":"additional","affiliation":[{"name":"Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeyeon","family":"Ju","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keun-Young","family":"Kim","sequence":"additional","affiliation":[{"name":"National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6196-0776","authenticated-orcid":false,"given":"Ziyao","family":"Shen","sequence":"additional","affiliation":[{"name":"Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-4225","authenticated-orcid":false,"given":"Dorota","family":"Skowronska-Krawczyk","sequence":"additional","affiliation":[{"name":"Center for Translational Vision Research, Department of Physiology, Biophysics & Ophthalmology, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-3202","authenticated-orcid":false,"given":"Robert N.","family":"Weinreb","sequence":"additional","affiliation":[{"name":"Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1117-4834","authenticated-orcid":false,"given":"Won-Kyu","family":"Ju","sequence":"additional","affiliation":[{"name":"Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1839","DOI":"10.1038\/cddis.2015.180","article-title":"DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma","volume":"6","author":"Kim","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1186\/s12974-018-1346-7","article-title":"Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma","volume":"15","author":"Inman","year":"2018","journal-title":"J. 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