In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors

Panayotis Pachnis, Zheng Wu, Brandon Faubert, Alpaslan Tasdogan, Wen Gu, Spencer Shelton, Ashley Solmonson, Aparna D. Rao, Akash K. Kaushik, Thomas J. Rogers, Jessalyn M. Ubellacker, Collette A. LaVigne, Chendong Yang, Bookyung Ko, Vijayashree Ramesh, Jessica Sudderth, Lauren G. Zacharias, Misty S. Martin-Sandoval, Duyen Do, Thomas P. MathewsZhiyu Zhao, Prashant Mishra, Sean J. Morrison, Ralph J. DeBerardinis

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)eabn9550
JournalScience Advances
Volume8
Issue number35
DOIs
StatePublished - Sep 2 2022

ASJC Scopus subject areas

  • General

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