SIRT 5 promotes IDH 2 desuccinylation and G6 PD deglutarylation to enhance cellular antioxidant defense

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 SIRT 5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 ( IDH 2) and glucose‐6‐phosphate dehydrogenase (G6 PD ), respectively, and thus activates both NADPH ‐producing enzymes. Moreover, we show that knockdown or knockout of SIRT 5 leads to high levels of cellular ROS . SIRT 5 inactivation leads to the inhibition of IDH 2 and G6 PD , thereby decreasing NADPH production, lowering GSH , impairing the ability to scavenge ROS , and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT 5‐dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH 2 desuccinylation and G6 PD deglutarylation.