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OPA1 is the sole fusion protein currently known to be situated in the inner mitochondrial membrane, which is pivotal for maintaining normal mitochondrial function. While it has already been demonstrated that mutations in OPA1 may lead to hereditary deafness, its involvement in the occurrence and development of ARHL has not been previously explored. In our study, we constructed D\u2010gal\u2010induced senescent HEI\u2010OC1 cells and the cochlea of C57BL\/6J mice with a mutated SUMOylation site of SIRT3 using CRISPR\/Cas9 technology. We found enhanced L\u2010OPA1 processing mediated by activated OMA1, and increased OPA1 acetylation resulting from reductions in SIRT3 levels in senescent HEI\u2010OC1 cells. Consequently, the fusion function of OPA1 was inhibited, leading to mitochondrial fission and pyroptosis in hair cells, ultimately exacerbating the aging process of hair cells. Our results suggest that the dysregulation of mitochondrial dynamics in cochlear hair cells in aged mice can be ameliorated by activating the SIRT3\/OPA1 signaling. This has the potential to alleviate the senescence of cochlear hair cells and reduce hearing loss in mice. Our study highlights the significant roles played by the quantities of long and short chains and the acetylation activity of OPA1 in the occurrence and development of ARHL. This finding offers new perspectives and potential targets for the prevention and treatment of ARHL.<\/jats:p>","DOI":"10.1111\/acel.14091","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T23:25:20Z","timestamp":1706138720000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Excessive processing and acetylation of OPA1 aggravate age\u2010related hearing loss via the dysregulation of mitochondrial dynamics"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4026-2366","authenticated-orcid":false,"given":"Andi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology &amp; Head and Neck Surgery, Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases  Shanghai China"},{"name":"Ear Institute Shanghai Jiao 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