The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration
Abstract Intervertebral disc degeneration (IVDD) is the primary contributor to a range of spinal diseases. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell (NPC) death and IVDD, but the underlying mechanisms remain u...
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Nature Publishing Group
2025-08-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-025-00449-6 |
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| author | Zhidi Lin Xiao Lu Guangyu Xu Jian Song Hongli Wang Xinlei Xia Feizhou Lu Jianyuan Jiang Wei Zhu Zuochong Yu Xiaosheng Ma Fei Zou |
| author_facet | Zhidi Lin Xiao Lu Guangyu Xu Jian Song Hongli Wang Xinlei Xia Feizhou Lu Jianyuan Jiang Wei Zhu Zuochong Yu Xiaosheng Ma Fei Zou |
| author_sort | Zhidi Lin |
| collection | DOAJ |
| description | Abstract Intervertebral disc degeneration (IVDD) is the primary contributor to a range of spinal diseases. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell (NPC) death and IVDD, but the underlying mechanisms remain unclear. Although the effects of Drp1 phosphorylation in IVDD have been studied, it is currently unknown if small ubiquitin-like modifications (SUMOylation) of Drp1 regulate IVDD. This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase (MAPL), a mitochondrial SUMO E3 ligase, during IVDD progression. The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing. The levels of total and mitochondrial SUMO1 conjugates were elevated with MAPL upregulation in TNF-α-treated NPCs. Additionally, mitochondrial fragmentation and dysfunction were induced by TNF-α stimulation. MAPL overexpression promoted mitochondrial SUMOylation and SUMO1 modification of Drp1, thereby facilitating the mitochondrial translocation of Drp1 and mitochondrial fission. MAPL-induced ROS accumulation and ΔΨm loss led to increased NPC apoptosis. Mutation of the SUMO-acceptor lysine residues of Drp1 hindered its SUMOylation and rescued the mitochondrial phenotypes caused by MAPL. SENP5 overexpression phenocopied MAPL silencing, negatively modulating the SUMO1 modification of Drp1 and mitochondrial fission in NPCs. In a rat IVDD model, forced expression of MAPL by using an adeno-associated virus (AAV) vector aggravated IVD tissue damage, whereas the knockdown of MAPL delayed IVDD progression. Our findings highlight the importance of SUMOylation in IVDD. The inhibition of MAPL-mediated Drp1 SUMOylation alleviates mitochondrial fission and limits IVDD development, providing a potential strategy for IVDD treatment. |
| format | Article |
| id | doaj-art-a367cb42292a48abaef13aa2dbb6b573 |
| institution | DOAJ |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-a367cb42292a48abaef13aa2dbb6b5732025-08-20T03:04:26ZengNature Publishing GroupBone Research2095-62312025-08-0113111310.1038/s41413-025-00449-6The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degenerationZhidi Lin0Xiao Lu1Guangyu Xu2Jian Song3Hongli Wang4Xinlei Xia5Feizhou Lu6Jianyuan Jiang7Wei Zhu8Zuochong Yu9Xiaosheng Ma10Fei Zou11Department of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Jinshan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityDepartment of Orthopedics, Huashan Hospital, Fudan UniversityAbstract Intervertebral disc degeneration (IVDD) is the primary contributor to a range of spinal diseases. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell (NPC) death and IVDD, but the underlying mechanisms remain unclear. Although the effects of Drp1 phosphorylation in IVDD have been studied, it is currently unknown if small ubiquitin-like modifications (SUMOylation) of Drp1 regulate IVDD. This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase (MAPL), a mitochondrial SUMO E3 ligase, during IVDD progression. The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing. The levels of total and mitochondrial SUMO1 conjugates were elevated with MAPL upregulation in TNF-α-treated NPCs. Additionally, mitochondrial fragmentation and dysfunction were induced by TNF-α stimulation. MAPL overexpression promoted mitochondrial SUMOylation and SUMO1 modification of Drp1, thereby facilitating the mitochondrial translocation of Drp1 and mitochondrial fission. MAPL-induced ROS accumulation and ΔΨm loss led to increased NPC apoptosis. Mutation of the SUMO-acceptor lysine residues of Drp1 hindered its SUMOylation and rescued the mitochondrial phenotypes caused by MAPL. SENP5 overexpression phenocopied MAPL silencing, negatively modulating the SUMO1 modification of Drp1 and mitochondrial fission in NPCs. In a rat IVDD model, forced expression of MAPL by using an adeno-associated virus (AAV) vector aggravated IVD tissue damage, whereas the knockdown of MAPL delayed IVDD progression. Our findings highlight the importance of SUMOylation in IVDD. The inhibition of MAPL-mediated Drp1 SUMOylation alleviates mitochondrial fission and limits IVDD development, providing a potential strategy for IVDD treatment.https://doi.org/10.1038/s41413-025-00449-6 |
| spellingShingle | Zhidi Lin Xiao Lu Guangyu Xu Jian Song Hongli Wang Xinlei Xia Feizhou Lu Jianyuan Jiang Wei Zhu Zuochong Yu Xiaosheng Ma Fei Zou The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration Bone Research |
| title | The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration |
| title_full | The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration |
| title_fullStr | The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration |
| title_full_unstemmed | The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration |
| title_short | The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration |
| title_sort | mitochondrial e3 ligase mapl sumoylates drp1 to facilitate mitochondrial fission in intervertebral disc degeneration |
| url | https://doi.org/10.1038/s41413-025-00449-6 |
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