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

TLDR

Mammalian cells rely on glucose and glutamine catabolism for growth, with PI3K/AKT signaling driving glucose addiction while the regulation of glutamine uptake and metabolism remains poorly understood. The study investigates how the oncogene Myc coordinates expression of genes that enable glutamine catabolism beyond the needs for protein and nucleotide biosynthesis. Myc activation induces a transcriptional program that promotes glutaminolysis, reprogramming mitochondria to depend on glutamine for TCA anaplerosis and cellular viability, reduces glucose contribution to the TCA cycle and phospholipid synthesis, and establishes glutamine addiction independent of PI3K/AKT signaling.

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.