SIRT3, a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial deacetylase, plays a crucial role in various cellular processes. It positively modulates energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. SIRT3 is also involved in pathways related to aging, inflammation, and cell death [1,2,3]. Genetic models, such as knockout (KO) mouse models, have been instrumental in studying its functions.

In Sirt3 null mice generated via Nuclease technology-mediated genome editing, Sirt3 deletion accelerated ovarian aging, as shown by decreased offspring sizes, follicle reserve, and oocyte markers, along with increased expression of aging and inflammation-related genes. There were also signs of mitochondrial dysfunction in aging oocytes and ovaries, indicating SIRT3's role in maintaining ovarian follicle reserve and oocyte quality in aging mice [5]. In global SIRT3 knockout post-traumatic osteoarthritis (OA) mice, there was an acceleration of pathological phenotypes like cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1 polarization, suggesting that SIRT3 prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis [4]. Sirt3-/-mice also showed more severe intestinal ischemia-reperfusion injury with increased ferroptosis, and resveratrol lost its ability to ameliorate this injury, indicating SIRT3's role in reducing ferroptosis during intestinal ischemia-reperfusion [6].

In conclusion, SIRT3 is essential for maintaining mitochondrial function, cellular redox balance, and plays a significant role in aging-related processes. The SIRT3 KO mouse models have revealed its importance in diseases such as ovarian senescence, osteoarthritis, and intestinal ischemia-reperfusion injury, providing valuable insights into potential therapeutic targets for these conditions.

References:

1. Zhou, Lei, Pinho, Ricardo, Gu, Yaodong, Radak, Zsolt. 2022. The Role of SIRT3 in Exercise and Aging. In Cells, 11, . doi:10.3390/cells11162596. https://pubmed.ncbi.nlm.nih.gov/36010672/

2. Diao, Zhiqing, Ji, Qianzhao, Wu, Zeming, Song, Moshi, Qu, Jing. . SIRT3 consolidates heterochromatin and counteracts senescence. In Nucleic acids research, 49, 4203-4219. doi:10.1093/nar/gkab161. https://pubmed.ncbi.nlm.nih.gov/33706382/

3. Ning, Yan, Dou, Xinyue, Wang, Zhichao, Han, Xin, Cao, Gang. 2024. SIRT3: A potential therapeutic target for liver fibrosis. In Pharmacology & therapeutics, 257, 108639. doi:10.1016/j.pharmthera.2024.108639. https://pubmed.ncbi.nlm.nih.gov/38561088/

4. Zhang, Yijian, Liu, Yang, Hou, Mingzhuang, He, Fan, Zhu, Xuesong. 2023. Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3-COX4I2 Axis Attenuates Osteoarthritis Progression. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2206144. doi:10.1002/advs.202206144. https://pubmed.ncbi.nlm.nih.gov/36683245/

5. Zhu, Jing, Yang, Qingling, Li, Hui, Lei, Min, Sun, Yingpu. 2022. Sirt3 deficiency accelerates ovarian senescence without affecting spermatogenesis in aging mice. In Free radical biology & medicine, 193, 511-525. doi:10.1016/j.freeradbiomed.2022.10.324. https://pubmed.ncbi.nlm.nih.gov/36336229/

6. Wang, Xingjie, Shen, Tianli, Lian, Jie, Sun, Xuejun, Li, Xuqi. 2023. Resveratrol reduces ROS-induced ferroptosis by activating SIRT3 and compensating the GSH/GPX4 pathway. In Molecular medicine (Cambridge, Mass.), 29, 137. doi:10.1186/s10020-023-00730-6. https://pubmed.ncbi.nlm.nih.gov/37858064/