Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction

David R. Wise, Ralph J. Deberardinis, Anthony Mancuso, Nabil Sayed, Xiao Yong Zhang, Harla K. Pfeiffer, Ilana Nissim, Evgueni Daikhin, Marc Yudkoff, Steven B. McMahon, Craig B. Thompson

Research output: Contribution to journalArticle

1102 Scopus citations

Abstract

Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.

Original languageEnglish (US)
Pages (from-to)18782-18787
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number48
DOIs
StatePublished - Dec 2 2008

Keywords

  • Cancer
  • Mitochondria

ASJC Scopus subject areas

  • General

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    Wise, D. R., Deberardinis, R. J., Mancuso, A., Sayed, N., Zhang, X. Y., Pfeiffer, H. K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S. B., & Thompson, C. B. (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proceedings of the National Academy of Sciences of the United States of America, 105(48), 18782-18787. https://doi.org/10.1073/pnas.0810199105