SIRT5 promotes IDH2 desuccinylation and G6PD 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 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.
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Lisha
L
Zhou
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Fang
F
Wang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Renqiang
R
Sun
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Xiufei
X
Chen
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Mengli
M
Zhang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Qi
Q
Xu
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Yi
Y
Wang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Shiwen
S
Wang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Yue
Y
Xiong
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Kun-Liang
KL
Guan
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Pengyuan
P
Yang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China hongxiuyu@fudan.edu.cn yedan@fudan.edu.cn.
Hongxiu
H
Yu
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China hongxiuyu@fudan.edu.cn yedan@fudan.edu.cn.
Dan
0000-0003-4848-0501
D
Ye
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D009249:NADP; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; C508544:SIRT5 protein, human; D037761:Sirtuins; D005978:Glutathione
NADPH; SIRT5; glutarylation; oxidative stress; succinylation