SIRT5促进异柠檬酸脱氢酶2（IDH2）去琥珀酰化和葡萄糖-6-磷酸脱氢酶（G6PD）去戊二酰化，以增强细胞抗氧化防御。
SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense.
作者信息
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
机构信息
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.
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.
出版信息
EMBO Rep. 2016 Jun;17(6):811-22. doi: 10.15252/embr.201541643. Epub 2016 Apr 9.
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.
线粒体活性氧（ROS）过量被认为是细胞氧化应激的主要原因。NADPH作为细胞内主要的还原剂，在维持谷胱甘肽处于还原形式GSH方面起关键作用，GSH可清除ROS，从而保护细胞免受氧化损伤。在此，我们报告SIRT5分别使异柠檬酸脱氢酶2（IDH2）和葡萄糖-6-磷酸脱氢酶（G6PD）去琥珀酰化和去戊二酰化，从而激活这两种产生NADPH的酶。此外，我们表明敲低或敲除SIRT5会导致细胞内ROS水平升高，SIRT5失活会导致IDH2和G6PD受到抑制，从而减少NADPH的产生，降低GSH水平，损害清除ROS的能力，并增加细胞对氧化应激的敏感性。我们的研究揭示了一种依赖SIRT5的机制，该机制通过促进IDH2去琥珀酰化和G6PD去戊二酰化来调节细胞NADPH稳态和氧化还原电位。
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