Abstract
Mitochondrial dynamics, including mitochondrial fission and fusion, are critical for maintaining mitochondrial functions. Evidence shows that TANK-binding kinase 1 (TBK1) regulates mitochondrial fusion and fission and then mitophagy. Since a previous study demonstrates a strong correlation between mitophagy and osteoarthritis (OA), we herein investigated the potential role of TBK1 in OA process and mitochondrial functions. We demonstrated a strong correlation between TBK1 and OA, evidenced by significantly downregulated expression of TBK1 in cartilage tissue samples of OA patients and in the chondrocytes of aged mice, as well as TNF-α-stimulated phosphorylation of TBK1 in primary mouse chondrocytes. TBK1 overexpression significantly attenuated TNF-α-induced apoptosis and abnormal mitochondrial function in primary mouse chondrocytes. Furthermore, TBK1 overexpression induced remodeling of mitochondrial morphology by directly phosphorylating dynamin-related protein 1 (DRP1) at Ser637, abolishing the fission of DRP1 and preventing its fragmentation function. Moreover, TBK1 recruitment and DRP1 phosphorylation at Ser637 was necessary for engulfing damaged mitochondria by autophagosomal membranes during mitophagy. Moreover, we demonstrated that APMK/ULK1 signaling contributed to TBK1 activation. In OA mouse models established by surgical destabilization of the medial meniscus, intraarticular injection of lentivirus-TBK1 significantly ameliorated cartilage degradation via regulation of autophagy and alleviation of cell apoptosis. In conclusion, our results suggest that the TBK1/DRP1 pathway is involved in OA and pharmacological targeting of the TBK1-DRP1 cascade provides prospective therapeutic benefits for the treatment of OA.
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Acknowledgements
This study was supported by grants from National Natural Science Foundation of China (81972150, 82172428), Wenzhou Inovation Team (Growth Factor Drug Development, No. 201801), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-028), Zhejiang Province Science and Technology Plan Research and Xinmiao Talent Program (Grant/Award Numbers: 2021R413082).
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SLH, JS designed the study and supervised the entire process. SLH and AM wrote the paper. YFS, XMJ, YXY, CZP performed the animal experiments. SLH, YFS, XMJ, YXY, CZP, YPC, SLL, and JJL performed the in vitro experiments. CZP, ZYL participated in data analysis.JX,XYW,SLH supervised and conceptualized the study. All authors read and approved the final paper.
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According to the Animal Care and Use Committee of Wenzhou Medical University, Wenzhou, Zhejiang Province, China, all surgical interventions, treatments and postoperative animal care protocols and procedures were entirely followed for conducting the research (ethical committee number: wydw2021-0583). The study complied with the Declaration of Helsinki and was approved by the Ethics Committee of The Second Affiliated Hospital of Wenzhou Medical University. All animals used in the study were cared for in accordance with the ethical guidelines on animal experimentation of Laboratory Animals of China National Institutes of Health. Healthy C57BL/6 mice were obtained from the Experimental Animal Center of Wenzhou Medical University, Zhejiang Province, China.
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Hu, Sl., Mamun, A.A., Shaw, J. et al. TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis. Acta Pharmacol Sin 44, 610–621 (2023). https://doi.org/10.1038/s41401-022-00967-7
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DOI: https://doi.org/10.1038/s41401-022-00967-7
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