SIRT4, a member of the sirtuin family, is an NAD+-dependent enzyme with reported functions in various biological processes. Sirtuins are known as longevity proteins, and SIRT4 has been associated with promoting DNA damage repair, participating in three-substance energy metabolism, inhibiting inflammatory reactions and apoptosis, and regulating mitochondrial function. It is also involved in processes related to age-related characteristics and diseases [1].

In mouse models, Sirt4 knockout decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes, revealing its role in safeguarding against cellular ammonia toxicity during amino acid catabolism [2]. In the context of chondrocyte senescence and osteoarthritis, knockdown of Sirt4 in chondrocytes promoted cellular senescence and cartilage degradation, while overexpression protected against these effects, suggesting its importance in maintaining chondrocyte and cartilage health [3]. Additionally, in intestinal fibrosis models, SIRT4 expression was decreased in a TGF-β dependent manner, and SIRT4 could resist glutaminolysis and alleviate intestinal fibrosis by facilitating GLS1 degradation [4].

In summary, SIRT4 plays crucial roles in multiple biological processes including metabolism, anti-inflammation, and cell-specific functions. Mouse knockout models have been instrumental in uncovering its functions in areas such as ammonia detoxification, chondrocyte senescence related to osteoarthritis, and intestinal fibrosis, providing potential therapeutic targets for related diseases.

References:

1. He, Ling, Liu, Qingcheng, Cheng, Jielong, Li, Jian, Tu, Huaijun. 2023. SIRT4 in ageing. In Biogerontology, 24, 347-362. doi:10.1007/s10522-023-10022-5. https://pubmed.ncbi.nlm.nih.gov/37067687/

2. Hu, Song-Hua, Feng, Yu-Yang, Yang, Yuan-Xin, Xu, Wei, Zhao, Shi-Min. 2023. Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle. In Nature metabolism, 5, 626-641. doi:10.1038/s42255-023-00784-0. https://pubmed.ncbi.nlm.nih.gov/37081161/

3. Lin, Shiyuan, Wu, Biao, Hu, Xinjia, Lu, Huading. 2024. Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction. In International journal of biological sciences, 20, 1256-1278. doi:10.7150/ijbs.85585. https://pubmed.ncbi.nlm.nih.gov/38385071/

4. Xue, Xinru, Zeng, Xi, Wu, Xiaoqian, Dai, Yue, Wei, Zhifeng. 2023. SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation. In Matrix biology : journal of the International Society for Matrix Biology, 122, 33-45. doi:10.1016/j.matbio.2023.08.001. https://pubmed.ncbi.nlm.nih.gov/37541633/