Reductive carboxylation supports growth in tumour cells with defective mitochondria
Open accessAbstract
Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.
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CHK1 inhibitors and glutaminase inhibitors are considered potential candidates for treating Myc-overexpressing cancers.
“Similarly, checkpoint kinase 1 (CHK1) inhibitors625–627 and glutaminase (GLS) inhibitors628–634 are also considered potential candidates for treating Myc-overexpressing cancers.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [630]
In the context of constitutive HIF-2α stabilization or defective mitochondrial electron transport chain, glutamine-derived α-KG is reductively carboxylated through consumption of NADPH by IDH2 to generate citrate.
“In the context of constitutive HIF-2α stabilization75 or a defective mitochondrial electron transport chain76, glutamine-derived α-KG is reductively carboxylated through the consumption of NADPH by IDH2 to generate citrate.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [76]
Reductive carboxylation is a critical pathway to support the growth of tumor cells under hypoxia.
“Previous reports showed that reductive carboxylation is a critical pathway to support the growth of tumor cells under hypoxia (Metallo, 2012; Mullen, 2012).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Mullen, 2012
Upregulation of the reductive carboxylation pathway enhances cancer cell proliferation.
“The upregulation of the reductive carboxylation pathway enhances cancer cells proliferation (Metallo, 2012; Mullen, 2012; Wise et al., 2011).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Mullen, 2012
Under conditions of hypoxia or impaired mitochondrial respiration, certain reactions of the TCA cycle reverse to support glutamine-dependent reductive carboxylation.
“For example, under conditions of hypoxia or impaired mitochondrial respiration, certain reactions of the TCA cycle reverse to support glutamine-dependent reductive carboxylation (92, 122, 123).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [123]
Citrate is generated by citrate synthase or through the reduction of α-ketoglutarate by isocitrate dehydrogenase.
“Citrate is generated by citrate synthase (CS) or through the reduction of α-ketoglutarate by isocitrate dehydrogenase (IDH).79–81”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [80]
Glutamine can contribute carbon to fatty acid synthesis via reductive carboxylation or oxidative glutaminolysis.
“Glutamine can contribute carbon to fatty acid synthesis via reductive carboxylation or oxidative glutaminolysis.”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Mullen et al., 2012
Reductive carboxylation is highly active in cells proliferating under hypoxia or with a compromised respiratory chain, while oxidative glutaminolysis has been observed in B cell lymphoma.
“The former pathway is highly active in cells proliferating under hypoxia or those with a compromised respiratory chain (Metallo et al., 2012; Mullen et al., 2012; Scott et al., 2011; Wise et al., 2011), while the latter pathway has been observed in B cell lymphoma (Le et al., 2012).”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Mullen et al., 2012
α-KG can be converted to citrate through reductive carboxylation under conditions of stress such as hypoxia or mitochondrial dysfunction.
“Although oxidation of glutamine-derived α-KG in the TCA cycle serves as a minor source of lipogenic acetyl-CoA under normal growth conditions, α-KG can be converted to citrate through reductive carboxylation under conditions of stress such as hypoxia or mitochondrial dysfunction (70–72).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [70]
These cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon in place of oxidative metabolism of both glucose and glutamine.
“In place of oxidative metabolism of both glucose and glutamine, these cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon (Le et al., 2012; Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Mullen et al., 2012
IDH-dependent reductive carboxylation plays a particularly important role in proliferating cells that exhibit decreased flux of glucose-derived pyruvate into mitochondria, in hypoxic cells or cells with defects in mitochondrial oxidative phosphorylation.
“Recently three independent reports implicated IDH-dependent reductive carboxylation as playing a particularly important role in proliferating cells that exhibit decreased flux of glucose-derived pyruvate into the mitochondria. This occurs in hypoxic cells or in cells harboring defects in mitochondrial oxidative phosphorylation (Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Mullen et al., 2012
Tumor cells with mutations in the TCA cycle or ETC, or with hypoxia-induced suppression of oxidative metabolism, use reductive carboxylation of α-KG to produce citrate and other precursors during growth.
“tumor cells with mutations in the TCA cycle or ETC (Mullen et al., 2011), or with hypoxia-induced suppression of oxidative metabolism (Metallo et al., 2011; Scott et al., 2011; Wise et al., 2011) use reductive carboxylation of α-KG to produce citrate and other precursors during growth.”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Mullen et al., 2011
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- Authors
- Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Northwestern University (US)
- National Institutes of Health (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Chandel, Navdeep S.
- DeBerardinis, Ralph J.
- ORCID
- Venue
- Nature
- Published
- 2011-11-20
- Volume
- 481
- Issue
- 7381
- Pages
- 385-388
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3262117
- OpenAlex
- W2092152920
- Cited by
- 1,328
- References
- 27
- Citations by year
- 2026: 81 · 2025: 92 · 2024: 63 · 2023: 70 · 2022: 107 · 2021: 107 · 2020: 91 · 2019: 88 · 2018: 82 · 2017: 84 · 2016: 96 · 2015: 98 · 2014: 99 · 2013: 86 · 2012: 80
- FWCI
- 29.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA123067, R01CA157996, T32CA009560)
- National Institute of General Medical Sciences (T32GM083831, T32GM008061)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK072565, K01DK078933, DK078933)
- 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 › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- reductive carboxylation, glutamine metabolism, IDH1, acetyl-CoA, lipogenesis, hypoxia, tumor growth, fumarate hydratase deficiency, renal carcinoma, TCA cycle
- MeSH terms
- Acetyl Coenzyme A, Animals, Carcinoma, Renal Cell, Electron Transport, Fumarate Hydratase, Glucose, Glutamine, Humans, Isocitrate Dehydrogenase, Kidney Neoplasms, Mitochondria, NADP, Neoplasms, Electron Transport Complex III, Cell Hypoxia, Citric Acid, Electron Transport Complex I, Cell Line, Tumor, Mice
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