{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T10:14:12Z","timestamp":1780481652111,"version":"3.54.1"},"reference-count":26,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Technology application advancement project","award":["21AH0103"],"award-info":[{"award-number":["21AH0103"]}]},{"name":"Pre-research Project","award":["21JMRH002"],"award-info":[{"award-number":["21JMRH002"]}]},{"name":"Discipline Development Program in Diving Medicine","award":["25XKQ0003"],"award-info":[{"award-number":["25XKQ0003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Central nervous system oxygen toxicity (CNS-OT) is a major complication of hyperbaric oxygen (HBO) characterized by seizures and neuronal damage, yet the underlying mechanisms remain incompletely understood. Using male Sprague Dawley rats (n = 6 per group) and HT22 neurons exposed to either HBO (6 ATA, 100% O2) or hyperbaric normoxia (HNO), our results demonstrate that HBO, but not HNO, caused mitochondrial structural damage and loss of mitochondrial membrane potential (\u0394\u03a8m). Transcriptomic analysis revealed enrichment of apoptosis and mitogen-activated protein kinase (MAPK) signaling pathways. Using HeLa cells stably overexpressing Parkin and Mito-Keima, a pH-sensitive mitochondrial probe system for monitoring mitophagy, we observed that mitophagic flux was initiated but proceeded too slowly to clear damaged mitochondria in a timely manner in HBO-exposed neurons. Pharmacological preconditioning to activate mitophagy enabled the prompt elimination of dysfunctional mitochondria and rescued HBO-induced mitochondrial dysfunction and cell death. In vivo, everolimus treatment promoted timely mitophagic clearance, prolonged seizure latency, attenuated \u0394\u03a8m loss, and suppressed p-p38 activation. These findings demonstrate that HBO exposure disrupts mitochondrial homeostasis and activates pro-apoptotic MAPK signaling. Meanwhile, endogenous mitophagy is initiated but fails to clear damaged mitochondria in a timely manner. Pre-activation of mitophagy by everolimus enables the timely clearance of damaged mitochondria, protecting against CNS-OT and highlighting a promising therapeutic strategy.<\/jats:p>","DOI":"10.3390\/ijms27114982","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:45:08Z","timestamp":1780404308000},"page":"4982","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pre-Activation of Mitophagy Protects Against Hyperbaric Oxygen-Induced Central Nervous System Oxygen Toxicity"],"prefix":"10.3390","volume":"27","author":[{"given":"Wei","family":"Ding","sequence":"first","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1855-5568","authenticated-orcid":false,"given":"Qi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-1787","authenticated-orcid":false,"given":"Guanning","family":"Wei","sequence":"additional","affiliation":[{"name":"Translational Medical Research Center, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyang","family":"Huang","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Shi","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"},{"name":"Translational Medical Research Center, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longfei","family":"Wang","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Ding","sequence":"additional","affiliation":[{"name":"Translational Medical Research Center, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqun","family":"Fang","sequence":"additional","affiliation":[{"name":"Naval Medical Center, Naval Medical University, Shanghai 200433, China"},{"name":"National Key Laboratory of Immunity and Inflammation, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","unstructured":"Jones, M.W., Brett, K., Han, N., Cooper, J.S., and Wyatt, H.A. 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