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SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth
Author(s) -
Yang Hui,
Zhou Lisha,
Shi Qian,
Zhao Yuzheng,
Lin Huaipeng,
Zhang Mengli,
Zhao Shimin,
Yang Yi,
Ling ZhiQiang,
Guan KunLiang,
Xiong Yue,
Ye Dan
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201591041
Subject(s) - chinese academy of sciences , china , biomedical sciences , biology , library science , political science , medicine , computer science , pathology , law
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 GOT 2 is acetylated and that deacetylation depends on mitochondrial SIRT 3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT 2 and MDH 2. The GOT 2 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, GOT 2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT 2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo . Finally, we show that GOT 2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT 3 expression. Our study uncovers a previously unknown mechanism by which GOT 2 acetylation stimulates the malate–aspartate NADH shuttle activity and oxidative protection.