Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction

• Published in: International journal of biological sciences Vol. 20; no. 4; pp. 1256 - 1278
• Main Authors: Lin, Shiyuan, Wu, Biao, Hu, Xinjia, Lu, Huading
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2024
• Subjects: Animals; Cartilage, Articular; Cellular Senescence - genetics; Chondrocytes; Down-Regulation; Mice; Mitochondrial Diseases - metabolism; Osteoarthritis - etiology; Protein Kinases - metabolism; Reactive Oxygen Species - metabolism; Research Paper; Sirtuins - genetics; Sirtuins - metabolism; Mitochondria; Reactive oxygen species; Senescence; Osteoarthritis; Sirt4
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.85585

Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of osteoarthritis (OA). Nevertheless, the precise molecular mechanisms underlying chondrocyte senescence remain poorly understood. To address this knowledge gap, we conducted an investigation into the involvement of Sirtuin 4 (Sirt4) in chondrocyte senescence. Our experimental findings revealed a downregulation of Sirt4 expression in TBHP-induced senescent chondrocytes in vitro, as well as in mouse OA cartilage. Additionally, we observed that the knockdown of Sirt4 in chondrocytes promoted cellular senescence and cartilage degradation, while the overexpression of Sirt4 protected the cells against TBHP-mediated senescence of chondrocytes and cartilage degradation. Moreover, our findings revealed elevated levels of reactive oxygen species (ROS), abnormal mitochondrial morphology, compromised mitochondrial membrane potential, and reduced ATP production in Sirt4 knockdown chondrocytes, indicative of mitochondrial dysfunction. Conversely, Sirt4 overexpression successfully mitigated TBHP-induced mitochondrial dysfunction. Further analysis revealed that Sirt4 downregulation impaired the cellular capacity to eliminate damaged mitochondria by inhibiting Pink1 in chondrocytes, thereby enhancing the accumulation of ROS and facilitating chondrocyte senescence. Notably, the overexpression of Pink1 counteracted the effects of Sirt4 knockdown on mitochondrial dysfunction. Importantly, our study demonstrated the promise of gene therapy employing a lentiviral vector encoding mouse Sirt4, as it successfully preserved the integrity of articular cartilage in mouse models of OA. In conclusion, our findings provide compelling evidence that the overexpression of Sirt4 enhances mitophagy, restores mitochondrial function, and protects against chondrocyte senescence, thereby offering a novel therapeutic target and potential strategy for the treatment of OA.