SIRT5 desuccinylating IDH2 to alleviate oxidative stress in bovine mammary epithelial cells induced by ammonia

Shikai Gao; Hanlin Yang; Jinru Dong; Anqi Li; Xinyi Zhang; Luya Liu; Guangyang Lu; Yang Liu; Guangming Zha; Kai Zhong; Heping Li; Yueying Wang; Shuang Guo

doi:10.1016/j.ijbiomac.2025.139619

SIRT5 desuccinylating IDH2 to alleviate oxidative stress in bovine mammary epithelial cells induced by ammonia

Int J Biol Macromol. 2025 Jan 7:139619. doi: 10.1016/j.ijbiomac.2025.139619. Online ahead of print.

Authors

Shikai Gao¹, Hanlin Yang¹, Jinru Dong¹, Anqi Li¹, Xinyi Zhang¹, Luya Liu¹, Guangyang Lu¹, Yang Liu¹, Guangming Zha¹, Kai Zhong¹, Heping Li², Yueying Wang³, Shuang Guo⁴

Affiliations

¹ Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China; Key Laboratory of Veterinary Biotechnology of Henan Province, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China.
² Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China; Key Laboratory of Veterinary Biotechnology of Henan Province, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China. Electronic address: liheping1972@126.com.
³ Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China; Key Laboratory of Veterinary Biotechnology of Henan Province, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China. Electronic address: yywang@henau.edu.cn.
⁴ Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China; Key Laboratory of Veterinary Biotechnology of Henan Province, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China. Electronic address: shuangshuang98@126.com.

PMID: 39788270
DOI: 10.1016/j.ijbiomac.2025.139619

Abstract

Ammonia can cause cells to produce a large amount of reactive oxygen species (ROS), leading to the oxidative stress of cells. As the main intracellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH) plays a crucial role in maintaining reduced glutathione (GSH), helping to remove ROS and protect cells from oxidative damage. Our study demonstrated that SIRT5 desuccinylated isocitrate dehydrogenase 2 (IDH2) to enhance its activity, resulting in increased NADPH production. Furthermore, we observed that SIRT5 overexpression alleviated ammonia-induced high levels of ROS in bovine mammary epithelial cells. This effect was achieved by activating IDH2 through SIRT5, which increased NADPH production and GSH levels, thereby improving the antioxidant capacity to scavenge ROS and reduce the susceptibility of cell to ROS. In conclusion, our findings revealed a SIRT5-dependent mechanism that modulated intracellular NADPH homeostasis to attenuate ammonia-induced oxidative stress by enhancing IDH2 enzymatic activity.

Keywords: IDH2; Oxidative stress; SIRT5.