TY - JOUR
T1 - In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors
AU - Pachnis, Panayotis
AU - Wu, Zheng
AU - Faubert, Brandon
AU - Tasdogan, Alpaslan
AU - Gu, Wen
AU - Shelton, Spencer
AU - Solmonson, Ashley
AU - Rao, Aparna D.
AU - Kaushik, Akash K.
AU - Rogers, Thomas J.
AU - Ubellacker, Jessalyn M.
AU - LaVigne, Collette A.
AU - Yang, Chendong
AU - Ko, Bookyung
AU - Ramesh, Vijayashree
AU - Sudderth, Jessica
AU - Zacharias, Lauren G.
AU - Martin-Sandoval, Misty S.
AU - Do, Duyen
AU - Mathews, Thomas P.
AU - Zhao, Zhiyu
AU - Mishra, Prashant
AU - Morrison, Sean J.
AU - DeBerardinis, Ralph J.
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/9
Y1 - 2022/9
N2 - In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.
AB - In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.
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U2 - 10.1126/sciadv.abn9550
DO - 10.1126/sciadv.abn9550
M3 - Article
C2 - 36044570
AN - SCOPUS:85136977324
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 35
M1 - eabn9550
ER -