SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense |
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| Authors: | Renqiang Sun Xiufei Chen Mengli Zhang Qi Xu Yi Wang Shiwen Wang Yue Xiong Kun‐Liang Guan Pengyuan Yang Hongxiu Yu Dan Ye |
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| Institution: | 1. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China;2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China;3. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China;4. Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China;5. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA;6. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA;7. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China |
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| Abstract: | 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. |
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| Keywords: | glutarylation
NADPH
oxidative stress SIRT5 succinylation |
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