文献类型：期刊文献

英文题名：SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth

作者：Yang, Hui[1];Zhou, Lisha[1];Shi, Qian[1];Zhao, Yuzheng[2];Lin, Huaipeng[1];Zhang, Mengli[1];Zhao, Shimin[1];Yang, Yi[2];Ling, Zhi-Qiang[3];Guan, Kun-Liang[1,4,5];Xiong, Yue[1,6];Ye, Dan[1]

机构：[1]Fudan Univ, State Key Lab Genet Engn, Collaborat Innovat Ctr Genet & Dev,Shanghai Med C, Sch Life Sci,Mol & Cell Biol Lab,Inst Biomed Sci, Shanghai 200433, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[3]Zhejiang Prov Canc Hosp, Zhejiang Canc Ctr, Zhejiang Canc Res Inst, Hangzhou, Zhejiang, Peoples R China;[4]Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA;[5]Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA;[6]Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

年份：2015

卷号：34

期号：8

起止页码：1110

外文期刊名：EMBO JOURNAL

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000352997000012)】；

基金：We thank the members of the Fudan MCB laboratory for discussions and support throughout this study. This work was supported by the 973 Program (No. 2012CB910303 to D.Y.; No. 2012CB910101 to K.L.G.), the NSFC grant (No. 81372198 to D.Y.), the NSFC Program of International Cooperation and Exchanges (No. 81120108016 to LXQ, Y.X.), and the Shanghai "Phosphor" Science Foundation, China (No. 14QA1400600 to D.Y.). This work was also supported by NIH grants (GM067113 and CA1638311 to Y.X.; CA132809 and CA108941 to K.L.G.).

语种：英文

外文关键词：acetylation; GOT2; malate-aspartate NADH shuttle; pancreatic cancer

摘要：The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate-aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD(+) redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate-aspartate NADH shuttle activity and oxidative protection.