SIRT5, a mitochondrial sirtuin, is an NAD-dependent protein lysine desuccinylase and demalonylase [6]. It plays a crucial role in regulating diverse metabolic pathways, including amino acid degradation, the tricarboxylic acid cycle, and fatty acid metabolism [5]. By removing succinyl and malonyl moieties from target lysines, SIRT5 impacts protein function and is involved in maintaining mitochondrial homeostasis [2]. Genetic models, such as gene knockout mouse models, are valuable tools for studying SIRT5's functions.

In various disease-related studies using knockout models: Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid production, promoting an immunosuppressive tumor microenvironment and hepatocarcinogenesis [1]. In pancreatic ductal adenocarcinoma (PDAC), genetic ablation of Sirt5 in mouse models promotes tumorigenesis through increased non-canonic use of glutamine via GOT1 [4]. Also, Sirt5 knockout in diabetic mice exacerbates cardiac dysfunction, hypertrophy, and lipotoxicity due to impaired fatty acid oxidation via CPT2 succinylation [3].

In conclusion, SIRT5 is a key regulator of metabolic pathways and mitochondrial homeostasis. Studies using Sirt5 KO/CKO mouse models have revealed its significance in diseases like hepatocellular carcinoma, PDAC, and diabetic cardiomyopathy. Understanding SIRT5's functions can provide new insights into disease mechanisms and potential therapeutic strategies.

References:

1. Sun, Renqiang, Zhang, Zhiyong, Bao, Ruoxuan, Wang, Pu, Ye, Dan. 2022. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. In Journal of hepatology, 77, 453-466. doi:10.1016/j.jhep.2022.02.030. https://pubmed.ncbi.nlm.nih.gov/35292350/

2. Mao, Jianxin, Wang, Di, Wang, Dong, Yang, Liu, Luo, Zhuojing. 2023. SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis. In Experimental & molecular medicine, 55, 253-268. doi:10.1038/s12276-023-00928-y. https://pubmed.ncbi.nlm.nih.gov/36653443/

3. Wu, Maoxiong, Tan, Jing, Cao, Zhengyu, Zhang, Haifeng, Chen, Yangxin. 2024. Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation. In Redox biology, 73, 103184. doi:10.1016/j.redox.2024.103184. https://pubmed.ncbi.nlm.nih.gov/38718533/

4. Hu, Tuo, Shukla, Surendra K, Vernucci, Enza, Tuveson, David, Singh, Pankaj K. 2021. Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression. In Gastroenterology, 161, 1584-1600. doi:10.1053/j.gastro.2021.06.045. https://pubmed.ncbi.nlm.nih.gov/34245764/

5. Park, Jeongsoon, Chen, Yue, Tishkoff, Daniel X, Lombard, David B, Zhao, Yingming. . SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. In Molecular cell, 50, 919-30. doi:10.1016/j.molcel.2013.06.001. https://pubmed.ncbi.nlm.nih.gov/23806337/

6. Du, Jintang, Zhou, Yeyun, Su, Xiaoyang, Hao, Quan, Lin, Hening. . Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. In Science (New York, N.Y.), 334, 806-9. doi:10.1126/science.1207861. https://pubmed.ncbi.nlm.nih.gov/22076378/