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Higher levels of homeostatic Ca\n                  <jats:sup>2+<\/jats:sup>\n                  and canonical Ca\n                  <jats:sup>2+<\/jats:sup>\n                  regulated signaling promote RGC survival in animal models of glaucoma and optic nerve injury. Mitochondrial dysfunction is also a hallmark of degenerating neurons, including RGCs. Here, we investigate the intersection of mitochondrial function, Ca\n                  <jats:sup>2+<\/jats:sup>\n                  homeostasis, and cellular resilience by performing an optic nerve crush model of RGC degeneration while monitoring and manipulating mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  levels (mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  ). We find that mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  is predicative of RGC survival in that surviving RGCs are enriched for higher homeostatic mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  levels. Mitochondrial dysfunction was observed where mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  was reduced in RGCs after injury, regardless of survival. We then examined the importance of higher mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  in surviving RGCs by altering mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  levels and Ca\n                  <jats:sup>2+<\/jats:sup>\n                  transit using pharmacological and AAV-mediated approaches. Paradoxically, treatment to decrease mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  increased survival to ONC. We then manipulated mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  permeability by altering the expression levels of the mitochondrial calcium uniporter (MCU) pore forming subunit that allows Ca\n                  <jats:sup>2+<\/jats:sup>\n                  to enter mitochondria from the cytoplasm. Overexpressing MCU reduced RGC survival to injury, while shRNA knockdown of MCU increased RGC survival. These results reveal a complex relationship between mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  and RGC degeneration and suggest that well-surviving RGCs may be under chronic mitochondrial stress due to higher homeostatic mito-Ca\n                  <jats:sup>2+<\/jats:sup>\n                  levels.\n                <\/jats:p>","DOI":"10.64898\/2026.05.13.724793","type":"posted-content","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T22:20:18Z","timestamp":1778883618000},"source":"Crossref","is-referenced-by-count":0,"title":["A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage"],"prefix":"10.64898","author":[{"given":"Sean","family":"McCracken","sequence":"first","affiliation":[{"name":"John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minglei","family":"Zhao","sequence":"additional","affiliation":[{"name":"John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyler","family":"Squirrell","sequence":"additional","affiliation":[{"name":"John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Zhao","sequence":"additional","affiliation":[{"name":"John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saman","family":"Behboodi Tanourlouee","sequence":"additional","affiliation":[{"name":"John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Aum","sequence":"additional","affiliation":[{"name":"John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-8925","authenticated-orcid":false,"given":"Philip R.","family":"Williams","sequence":"additional","affiliation":[{"name":"John F. 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