2. Academic Validation
  3. TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis

TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis

  • Acta Pharmacol Sin. 2022 Aug 25. doi: 10.1038/s41401-022-00967-7.
Sun-Li Hu 1 2 3,  Abdullah Al Mamun 2,  Jian Shaw 1 2 3,  Sun-Long Li 3,  Yi-Feng Shi 3,  Xue-Man Jin 3,  Ying-Xin Yu 3,  Chao-Zhi Pang 3,  Ze-Yang Li 3,  Jia-Jie Lu 3,  Yue-Piao Cai 1 2,  Xiang-Yang Wang 4 5 6,  Jian Xiao 7 8
Affiliations

Affiliations

  • 1 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 2 Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 3 The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China.
  • 4 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. xiangyangwang@wmu.edu.cn.
  • 5 Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. xiangyangwang@wmu.edu.cn.
  • 6 The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China. xiangyangwang@wmu.edu.cn.
  • 7 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. xfxj2000@126.com.
  • 8 Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. xfxj2000@126.com.
PMID: 36008706 DOI: 10.1038/s41401-022-00967-7
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.

Keywords

APMK/ULK1; TBK1/DRP1 axis; malvidin-3-O-arabinoside; mitochondria morphology; mitophagy; osteoarthritis.

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