SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense

• Published in: EMBO reports Vol. 17; no. 6; pp. 811 - 822
• Main Authors: Zhou, Lisha, Wang, Fang, Sun, Renqiang, Chen, Xiufei, Zhang, Mengli, Xu, Qi, Wang, Yi, Wang, Shiwen, Xiong, Yue, Guan, Kun-Liang, Yang, Pengyuan, Yu, Hongxiu, Ye, Dan
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.06.2016; Nature Publishing Group UK; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; Cell Line; Cell Survival; Dehydrogenase; Dehydrogenases; EMBO21; EMBO29; EMBO31; Enzymatic activity; Enzymes; Gene Knockdown Techniques; Glucosephosphate Dehydrogenase - metabolism; glutarylation; Glutathione - metabolism; Homeostasis; Humans; Inactivation; Isocitrate Dehydrogenase - chemistry; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Mice; Mice, Knockout; Mitochondria - metabolism; Mutation; NADP - metabolism; NADPH; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Protein Processing, Post-Translational; Reactive Oxygen Species - metabolism; Redox potential; Scientific Report; Scientific Reports; SIRT5; Sirtuins - chemistry; Sirtuins - genetics; Sirtuins - metabolism; succinylation; NADPH; glutarylation; SIRT5; succinylation; oxidative stress
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201541643

Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose‐6‐phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH‐producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS. SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5‐dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation. Synopsis This study shows that SIRT5 desuccinylates and deglutarylates IDH2 and G6PD, respectively, and activates both enzymes to maintain cellular NADPH homeostasis and to enhance cellular antioxidant defense. SIRT5 protects cells from oxidative damage by controlling NADPH homeostasis. SIRT5 catalyzes IDH2 desuccinylation and G6PD deglutarylation to stimulate their enzyme activity. SIRT5 desuccinylase activity is triggered by oxidative stimuli. Graphical Abstract This study shows that SIRT5 desuccinylates and deglutarylates IDH2 and G6PD, respectively, and activates both enzymes to maintain cellular NADPH homeostasis and to enhance cellular antioxidant defense.