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Mol Cell. 2014 Nov 6;56(3):414-24. doi: 10.1016/j.molcel.2014.09.025. Epub 2014 Oct 21.

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

Author information

1
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
2
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
3
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
4
McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
5
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
6
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA. Electronic address: Ralph.deberardinis@utsouthwestern.edu.

Abstract

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 reroutes 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.

PMID:
25458842
PMCID:
PMC4268166
DOI:
10.1016/j.molcel.2014.09.025
[Indexed for MEDLINE]
Free PMC Article
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