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Aberrant mitochondrial fission induced by dynamin\u2010related protein 1 (DRP1) causes mitochondrial dysfunction in dopaminergic (DA) neurons. However, the mechanism of DRP1 activation and its role in PD progression remain unclear. In this study, Mass spectrometry analysis is performed and identified a significant increased DRP1 acetylation at lysine residue 711 (K711) in the mitochondria under oxidative stress. Enhanced DRP1\n                    <jats:sup>K711<\/jats:sup>\n                    acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1\n                    <jats:sup>K711<\/jats:sup>\n                    acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)\u20103 in deacetylating DRP1\n                    <jats:sup>K711<\/jats:sup>\n                    , thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1\n                    <jats:sup>K711<\/jats:sup>\n                    acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1\n                    <jats:sup>K711<\/jats:sup>\n                    acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3\u2010mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202411235","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T06:26:06Z","timestamp":1740032766000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["SIRT3\u2010Mediated Deacetylation of DRP1\n                    <sup>K711<\/sup>\n                    Prevents Mitochondrial Dysfunction in Parkinson's Disease"],"prefix":"10.1002","volume":"12","author":[{"given":"Ye","family":"Xi","sequence":"first","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Experimental Surgery Tangdu Hospital Fourth Military Medical University  Xi'an Shaanxi 710038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayun","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tangdu Hospital Fourth Military Medical University  Xi'an Shaanxi 710038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifan","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Biophysics Institute of Neuroscience NHC and CAMS Key Laboratory of Medical Neurobiology Zhejiang University School of Medicine  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghui","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Experimental Surgery Tangdu Hospital Fourth Military Medical University  Xi'an Shaanxi 710038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience College of Medicine Xiamen University Xiamen  Fujian 361105 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3210-9567","authenticated-orcid":false,"given":"Shengxi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30230-7"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26966"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.04.004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.170"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-016-0060-6"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.10.020"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3013"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.01.013"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20170104"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104553"},{"key":"e_1_2_9_12_1","first-page":"1201","volume":"34","author":"Chang C. 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