SIRT5, a mitochondrial sirtuin, is an NAD-dependent protein lysine desuccinylase and demalonylase [7]. It plays a crucial role in regulating various metabolic pathways, such as amino acid degradation, the tricarboxylic acid cycle, and fatty acid metabolism, by removing succinyl and malonyl moieties from target lysines [6]. Genetic models, like KO/CKO mouse models, have been instrumental in studying SIRT5's functions in vivo.

In non-liver cells, SIRT5-silenced cells showed increased ammonia production, while overexpressing cells had decreased production. SIRT5 regulates ammonia production by controlling glutamine metabolism, and ammonia-induced autophagy and mitophagy are also regulated by SIRT5 [1]. In pancreatic ductal adenocarcinoma (PDAC), genetic ablation of Sirt5 in mouse models promoted tumorigenesis, as SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1 [5]. In hepatocellular carcinoma (HCC), Sirt5 deficiency in mice increased bile acid production, creating an immunosuppressive tumor microenvironment that favored tumor-initiating cells [2]. In intervertebral disc degeneration (IDD), knockdown of Sirt5 in rat nucleus pulposus tissues aggravated apoptosis and dysfunction of NP cells, while overexpression alleviated these effects [3]. In diabetic cardiomyopathy, Sirt5 deficiency impaired fatty acid oxidation (FAO) in the diabetic heart through the succinylation of Lys424 in carnitine palmitoyltransferase 2 (CPT2), leading to cardiac lipotoxicity [4].

In conclusion, SIRT5 is a key regulator in multiple metabolic pathways. KO/CKO mouse models have revealed its significance in diseases like PDAC, HCC, IDD, and diabetic cardiomyopathy. By modulating protein succinylation, SIRT5 affects various cellular functions, highlighting its potential as a therapeutic target for these diseases.

References:

1. Polletta, Lucia, Vernucci, Enza, Carnevale, Ilaria, Russo, Matteo A, Tafani, Marco. . SIRT5 regulation of ammonia-induced autophagy and mitophagy. In Autophagy, 11, 253-70. doi:10.1080/15548627.2015.1009778. https://pubmed.ncbi.nlm.nih.gov/25700560/

2. 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/

3. 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/

4. 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/

5. 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/

6. 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/

7. 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/