SIRT5 desuccinylates ME2 to suppress oxidative stress in bovine mammary epithelial cells

Excessive accumulation of Reactive Oxygen Species (ROS) in mitochondria is a key factor in inducing cellular oxidative stress. NADPH serves as a critical reducing equivalent for maintaining glutathione (GSH) in its reduced state, which is essential for ROS scavenging and cellular protection. Here, we demonstrate that SIRT5 desuccinylates and activates malic enzyme 2 (ME2), thereby increasing intracellular NADPH and GSH levels. This enhanced antioxidant capacity effectively neutralizes excess ROS induced by lipoteichoic acid (LTA) in bovine mammary epithelial cells. Concomitantly, SIRT5-mediated ME2 activation improves mitochondrial membrane potential, ATP production, and the expression of mitochondrial biogenesis-related genes. Conversely, genetic ablation of SIRT5 or pharmacological inhibition of ME2 activity severely compromises cellular antioxidant defense and sensitizes cells to oxidative stress, indicating that ME2 is indispensable for the antioxidative function of SIRT5. Collectively, our study reveals a previously unrecognized mechanism in mammary epithelium whereby SIRT5 enhances antioxidant capacity and preserves mitochondrial function via ME2 desuccinylation. These findings highlight the SIRT5-ME2 axis as a potential therapeutic target for mitigating oxidative damage and preventing mastitis.