ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion
Abstract The effectiveness of cranial suture expansion therapy hinges on the timely and adequate regeneration of bone tissue in response to mechanical stimuli. To optimize clinical outcomes and prevent post-expansion relapse, we delved into the underlying mechanisms governing bone remodeling during...
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Nature Publishing Group
2025-06-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-025-00427-y |
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| author | Jingyi Cai Ziyang Min Chaoyuan Li Zhihe Zhao Jun Liu Dian Jing |
| author_facet | Jingyi Cai Ziyang Min Chaoyuan Li Zhihe Zhao Jun Liu Dian Jing |
| author_sort | Jingyi Cai |
| collection | DOAJ |
| description | Abstract The effectiveness of cranial suture expansion therapy hinges on the timely and adequate regeneration of bone tissue in response to mechanical stimuli. To optimize clinical outcomes and prevent post-expansion relapse, we delved into the underlying mechanisms governing bone remodeling during the processes of suture expansion and relapse. Our findings revealed that in vitro stretching bolstered mesenchymal stem cells’ antioxidative and osteogenic capacity by orchestrating mitochondrial activities, which governed by force-induced endoplasmic reticulum (ER) stress. Nonetheless, this signal transduction occurred through the activation of protein kinase R-like ER kinase (PERK) at the ER-mitochondria interface, rather than ER-mitochondria calcium flow as previously reported. Subsequently, PERK activation triggered TFEB translocation to the nucleus, thus regulating mitochondrial dynamics transcriptionally. Assessment of the mitochondrial pool during expansion and relapse unveiled a sequential, two-phase regulation governed by the ER stress/p-PERK/TFEB signaling cascade. Initially, PERK activation facilitated TFEB nuclear localization, stimulating mitochondrial biogenesis through PGC1-α, thereby addressing energy demands during the initial phase. Subsequently, TFEB shifted focus towards ensuring adequate mitophagy for mitochondrial quality maintenance during the remodeling process. Premature withdrawal of expanding force disrupted this sequential regulation, leading to compromised mitophagy and the accumulation of dysfunctional mitochondria, culminating in suboptimal bone regeneration and relapse. Notably, pharmacological activation of mitophagy effectively mitigated relapse and attenuated bone loss, while its inhibition impeded anticipated bone growth in remodeling progress. Conclusively, we elucidated the ER stress/p-PERK/TFEB signaling orchestrated sequential mitochondria biogenesis and mitophagy under mechanical stretch, thus ensuring antioxidative capacity and osteogenic potential of cranial suture tissues. |
| format | Article |
| id | doaj-art-e39dcec49ea54297b8ae49f6a7ac14dc |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-e39dcec49ea54297b8ae49f6a7ac14dc2025-08-20T03:31:44ZengNature Publishing GroupBone Research2095-62312025-06-0113111410.1038/s41413-025-00427-yER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansionJingyi Cai0Ziyang Min1Chaoyuan Li2Zhihe Zhao3Jun Liu4Dian Jing5 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, Sichuan University State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, Sichuan UniversityDepartment of Implantology, School and Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, Sichuan University State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, Sichuan UniversityDepartment of Orthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of StomatologyAbstract The effectiveness of cranial suture expansion therapy hinges on the timely and adequate regeneration of bone tissue in response to mechanical stimuli. To optimize clinical outcomes and prevent post-expansion relapse, we delved into the underlying mechanisms governing bone remodeling during the processes of suture expansion and relapse. Our findings revealed that in vitro stretching bolstered mesenchymal stem cells’ antioxidative and osteogenic capacity by orchestrating mitochondrial activities, which governed by force-induced endoplasmic reticulum (ER) stress. Nonetheless, this signal transduction occurred through the activation of protein kinase R-like ER kinase (PERK) at the ER-mitochondria interface, rather than ER-mitochondria calcium flow as previously reported. Subsequently, PERK activation triggered TFEB translocation to the nucleus, thus regulating mitochondrial dynamics transcriptionally. Assessment of the mitochondrial pool during expansion and relapse unveiled a sequential, two-phase regulation governed by the ER stress/p-PERK/TFEB signaling cascade. Initially, PERK activation facilitated TFEB nuclear localization, stimulating mitochondrial biogenesis through PGC1-α, thereby addressing energy demands during the initial phase. Subsequently, TFEB shifted focus towards ensuring adequate mitophagy for mitochondrial quality maintenance during the remodeling process. Premature withdrawal of expanding force disrupted this sequential regulation, leading to compromised mitophagy and the accumulation of dysfunctional mitochondria, culminating in suboptimal bone regeneration and relapse. Notably, pharmacological activation of mitophagy effectively mitigated relapse and attenuated bone loss, while its inhibition impeded anticipated bone growth in remodeling progress. Conclusively, we elucidated the ER stress/p-PERK/TFEB signaling orchestrated sequential mitochondria biogenesis and mitophagy under mechanical stretch, thus ensuring antioxidative capacity and osteogenic potential of cranial suture tissues.https://doi.org/10.1038/s41413-025-00427-y |
| spellingShingle | Jingyi Cai Ziyang Min Chaoyuan Li Zhihe Zhao Jun Liu Dian Jing ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion Bone Research |
| title | ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion |
| title_full | ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion |
| title_fullStr | ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion |
| title_full_unstemmed | ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion |
| title_short | ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion |
| title_sort | er induced perk tfeb cascade sequentially modulates mitochondrial dynamics during cranial suture expansion |
| url | https://doi.org/10.1038/s41413-025-00427-y |
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