Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport
Open accessAbstract
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.
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Under normal and glucose-replete conditions, transamination is the dominant reaction driving glutamine anaplerosis in cultured cells.
“However, under normal and glucose-replete conditions, transamination is the dominant reaction that drives glutamine anaplerosis in cultured cells (79, 80, 81, 82).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [79]
Glutamine anaplerosis sustains TCA cycle intermediates in conditions of limiting glucose and MPC inhibition.
“Glutamine anaplerosis sustains TCA cycle intermediates in conditions of limiting glucose and MPC inhibition, demonstrating the potential flexibility of these metabolic nodes.34,35”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [34]
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- Authors
- Yang, C., Ko, B., Hensley, C. T., Jiang, L., Wasti, A. T., Kim, J., Sudderth, J., Calvaruso, M. A., Lumata, L., Mitsche, M., Rutter, J., Merritt, M. E., & DeBerardinis, R. J.
- Affiliations
- Children's Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- University of Utah (US)
- Corresponding author
- DeBerardinis, Ralph J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 56
- Issue
- 3
- Pages
- 414-424
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2102186262
- Cited by
- 679
- References
- 49
- Citations by year
- 2026: 50 · 2025: 68 · 2024: 61 · 2023: 53 · 2022: 70 · 2021: 91 · 2020: 51 · 2019: 69 · 2018: 43 · 2017: 39 · 2016: 51 · 2015: 30 · 2014: 2
- FWCI
- 13.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute ((P50-CA70907, CA157996, P50CA070907, R01CA157996)
- National Institute of General Medical Sciences (T32GM007062, K01GM109317)
- National Institute of Biomedical Imaging and Bioengineering (P41EB015908, R21EB016197)
- National Center for Research Resources (P41RR002584, RR‐02584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glutamine oxidation, glutamate dehydrogenase, mitochondrial pyruvate carrier, TCA cycle, acetyl-CoA formation, oxaloacetate, glutaminolysis, metabolic stress, synthetic lethality, tumor growth, cell survival, glucose deprivation
- MeSH terms
- Acetyl Coenzyme A, Animals, Antineoplastic Agents, Biological Transport, Catechin, Cell Survival, Citric Acid Cycle, Coumaric Acids, Glucose, Glutamine, Humans, Male, Mice, Nude, Mitochondria, Oxidation-Reduction, Sugar Alcohol Dehydrogenases, Pyruvic Acid, Citric Acid, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Lipid Metabolism
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