Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport

By Chendong Yang, Bookyung Ko, C. Hensley, Lei Jiang, Ajla T. Wasti, Jiyeon Kim, J. Sudderth, M. Calvaruso, L. Lumata, Matthew A. Mitsche and 3 more. Molecules and Cells, 2014

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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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fb083cec048404289385c5e775e7865a0afd5ad0

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Citations in the corpus

Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “Nonetheless, blockade of the mitochondrial pyruvate transport activates GDH and redirects glutamine metabolism to generate both oxaloacetate and acetyl-CoA, inducing glutamine-dependent lipid synthesis [119].”
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “For example, restricted access to pyruvate reveals the ability of cancer cells to convert glutamine into acetyl-CoA by carboxylation, maintaining both energetic and anabolic needs (Yang et al., 2014).”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, background): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Acetyl coenzyme A: a central metabolite and second messenger. (2015, background): “First, cytosolic acetyl-CoA can originate from glutamine reductive carboxylation, especially when glycolysis is blocked (Yang et al., 2014), in hypoxic conditions (Metallo et al., 2012), Cell Metabolism 21, June 2, 2015 ª2015 Elsevier Inc. 807 or in the presence of mitochondrial defects (Mullen et…”