Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration
Abstract Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cel...
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| Format: | Article |
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Nature Publishing Group
2025-06-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-025-00441-0 |
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| author | Zhangrong Cheng Haiyang Gao Pengzhi Shi Anran Zhang Xianglong Chen Yuhang Chen Weikang Gan Kangcheng Zhao Shuai Li Cao Yang Yukun Zhang |
| author_facet | Zhangrong Cheng Haiyang Gao Pengzhi Shi Anran Zhang Xianglong Chen Yuhang Chen Weikang Gan Kangcheng Zhao Shuai Li Cao Yang Yukun Zhang |
| author_sort | Zhangrong Cheng |
| collection | DOAJ |
| description | Abstract Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies. |
| format | Article |
| id | doaj-art-4a99e79ca5994505bcb36be9b1d48b64 |
| institution | OA Journals |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-4a99e79ca5994505bcb36be9b1d48b642025-08-20T02:06:19ZengNature Publishing GroupBone Research2095-62312025-06-0113111910.1038/s41413-025-00441-0Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degenerationZhangrong Cheng0Haiyang Gao1Pengzhi Shi2Anran Zhang3Xianglong Chen4Yuhang Chen5Weikang Gan6Kangcheng Zhao7Shuai Li8Cao Yang9Yukun Zhang10Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.https://doi.org/10.1038/s41413-025-00441-0 |
| spellingShingle | Zhangrong Cheng Haiyang Gao Pengzhi Shi Anran Zhang Xianglong Chen Yuhang Chen Weikang Gan Kangcheng Zhao Shuai Li Cao Yang Yukun Zhang Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration Bone Research |
| title | Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration |
| title_full | Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration |
| title_fullStr | Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration |
| title_full_unstemmed | Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration |
| title_short | Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration |
| title_sort | chaperone mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration |
| url | https://doi.org/10.1038/s41413-025-00441-0 |
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