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SIRT 5 promotes IDH 2 desuccinylation and G6 PD deglutarylation to enhance cellular antioxidant defense
Author(s) -
Zhou Lisha,
Wang Fang,
Sun Renqiang,
Chen Xiufei,
Zhang Mengli,
Xu Qi,
Wang Yi,
Wang Shiwen,
Xiong Yue,
Guan KunLiang,
Yang Pengyuan,
Yu Hongxiu,
Ye Dan
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541643
Subject(s) - reactive oxygen species , oxidative stress , glutathione , microbiology and biotechnology , isocitrate dehydrogenase , chemistry , biochemistry , antioxidant , oxidative phosphorylation , mitochondrial ros , mitochondrion , idh2 , gene knockdown , enzyme , biology , idh1 , apoptosis , mutant , gene
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.