Glutamine Oxidation Maintains the TCA Cycle and Cell Survival during Impaired Mitochondrial Pyruvate Transport

Abstract

Summary Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydrogenase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and glutamine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and re-routes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria.

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

“…Increased oxidative glutaminolysis and reductive carboxylation upon MPC inhibition were observed in transformed cell lines, although the relative contributions of these fates of glutamine were dependent on the cell line and growth conditions (59,60). Glutamine anaplerosis supports cellular proliferation in transformed cells and inhibition of glutaminase-or glutamate dehydrogenase-sensitized cells to growth inhibition upon treatment with UK-5099 (60). Analogous to the differences in glutamine metabolism observed in primary and transformed cultured cells, glutamine seems to play a more significant anaplerotic role in the brain than in the fetal liver, as glutamine was the second most downregulated metabolite in the Mpc1 KI/KI brain.…”

“…We found that alanine provides a robust anaplerotic substrate in several cellular models of MPC deficiency, as well as in vivo in embryonic brain and liver. It has been demonstrated that Mpc2-deficient mitochondria exhibit no alterations in alanine uptake (62), and decreased steady-state alanine concentrations have been observed in several MPC-deficient cell models and in vivo (59,60,62). The decrease in steadystate alanine has been interpreted as a result of most cellular alanine being derived from mitochondrial pyruvate, but we sought to test the flux of alanine itself.…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Specific chemical inhibition of pyruvate transport into the mitochondrion synergizes with inhibition of glutaminolysis to cause increased death 250 .…”

Evaluation of non-volatile taste components in commercial soy sauces

“…Pyruvate might be used as the beginning of the TCA cycle and as a raw material of free amino acid. [25] Acetylpropionic acid was not detected either, which was reported to be absence from brewed soy sauce, and was considered a judgement factor for Japanesestyle fermented soy sauce. [26] These organic acids influence the acidity of soy sauces and ensure a balance in taste.…”