SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease
Abstract Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin‐related protein 1 (DRP1) causes mitochondrial dysfunction in dopaminergic (DA) neurons. However, the mechanism of DRP1 activat...
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| Format: | Article |
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411235 |
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| author | Ye Xi Kai Tao Xiaomin Wen Dayun Feng Zifan Mai Hui Ding Honghui Mao Mingming Wang Qian Yang Jie Xiang Jie Zhang Shengxi Wu |
| author_facet | Ye Xi Kai Tao Xiaomin Wen Dayun Feng Zifan Mai Hui Ding Honghui Mao Mingming Wang Qian Yang Jie Xiang Jie Zhang Shengxi Wu |
| author_sort | Ye Xi |
| collection | DOAJ |
| description | Abstract Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin‐related 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 DRP1K711 acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1K711 acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)‐3 in deacetylating DRP1K711, thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1K711 acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1K711 acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3‐mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment. |
| format | Article |
| id | doaj-art-7ab3af24dc7c4a64b5aa2fc13215ad8a |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-7ab3af24dc7c4a64b5aa2fc13215ad8a2025-08-20T02:15:07ZengWileyAdvanced Science2198-38442025-05-011217n/an/a10.1002/advs.202411235SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's DiseaseYe Xi0Kai Tao1Xiaomin Wen2Dayun Feng3Zifan Mai4Hui Ding5Honghui Mao6Mingming Wang7Qian Yang8Jie Xiang9Jie Zhang10Shengxi Wu11Department of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Experimental Surgery Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi 710038 ChinaDepartment of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi 710038 ChinaDepartment of Biophysics Institute of Neuroscience NHC and CAMS Key Laboratory of Medical Neurobiology Zhejiang University School of Medicine Hangzhou 310058 ChinaDepartment of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Experimental Surgery Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi 710038 ChinaDepartment of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaInstitute of Neuroscience College of Medicine Xiamen University Xiamen Fujian 361105 ChinaDepartment of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi 710032 ChinaAbstract Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin‐related 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 DRP1K711 acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1K711 acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)‐3 in deacetylating DRP1K711, thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1K711 acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1K711 acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3‐mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment.https://doi.org/10.1002/advs.202411235acetylationDRP1K711mitochondrial dysfunctionoxidative stressParkinson's diseaseSIRT3 |
| spellingShingle | Ye Xi Kai Tao Xiaomin Wen Dayun Feng Zifan Mai Hui Ding Honghui Mao Mingming Wang Qian Yang Jie Xiang Jie Zhang Shengxi Wu SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease Advanced Science acetylation DRP1K711 mitochondrial dysfunction oxidative stress Parkinson's disease SIRT3 |
| title | SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease |
| title_full | SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease |
| title_fullStr | SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease |
| title_full_unstemmed | SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease |
| title_short | SIRT3‐Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease |
| title_sort | sirt3 mediated deacetylation of drp1k711 prevents mitochondrial dysfunction in parkinson s disease |
| topic | acetylation DRP1K711 mitochondrial dysfunction oxidative stress Parkinson's disease SIRT3 |
| url | https://doi.org/10.1002/advs.202411235 |
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