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Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Open accessAbstract
Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.
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In the citing paper
“Both HIF-1α and HIF-2α activation promotes the upregulation of the glutamine transporter, SLC38A2, which increases the dependency of cells to glutamine and correlates with poorer survival in patients with breast cancer [58]”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [58]
Experimental — accuracy not yet measuredIn the citing paper
“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 [631]
In the citing paper
“Citrate, generated by reductive carboxylation of α-KG, is especially crucial for lipid synthesis under low-oxygen conditions24,25.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [24]
In the citing paper
“and switch the fate of glutamine from the oxidative pathway into the reductive carboxylation pathway24.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [24]
In the citing paper
“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 [75]
In the citing paper
“Glutamine acts as an alternative fuel for fatty acid synthesis, supplying citrate via mitochondrial reductive carboxylation, especially under hypoxic conditions74,75.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [75]
In the citing paper
“Alternatively, proliferating cells under hypoxia have been reported to predominantly reductively carboxylate glutamine generated α-ketoglutarate through IDH 1/2 to generate M5 citrate (Figure 4A) (Metallo, 2012).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Metallo, 2012
In the citing paper
“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 Metallo, 2012
In the citing paper
“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 Metallo, 2012
In the citing paper
“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 [122]
In the citing paper
“In a process referred to as reductive carboxylation, a section of the TCA cycle reverses itself, converting α-ketoglutarate into citrate, which can be then used to generate a source of cytosolic acetyl-CoA (Metallo et al., 2012; Wise et al., 2011).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Metallo et al., 2012
In the citing paper
“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 [79]
In the citing paper
“Citrate levels, however, were markedly decreased in Mpc1KD or Mpc2KD (Mpc1/2KD) cells, as this metabolite is generated predominantly from pyruvate-derived AcCoA under normal growth conditions (Metallo et al., 2012).”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Metallo et al., 2012
In the citing paper
“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 Metallo et al., 2012
In the citing paper
“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 Metallo et al., 2012
In the citing paper
“This switch to reductive versus oxidative metabolism of α-KG is regulated in part by HIF-1α (71, 72), although the exact mechanism by which HIF-1α does so remains unclear.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [71]
In the citing paper
“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 [71]
In the citing paper
“The work from Metallo and colleagues (71) suggests that T cells can use reductive glutamine metabolism for fatty acid biosynthesis under hypoxic conditions.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [71]
In the citing paper
“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 Metallo et al., 2012
In the citing paper
“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 Metallo et al., 2012
In the citing paper
“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 Metallo et al., 2011
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Metadata
- Authors
- Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., Kelleher, J. K., Vander Heiden, M. G., Iliopoulos, O., & Stephanopoulos, G.
- Affiliations
- Massachusetts Institute of Technology (US)
- Massachusetts General Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Iliopoulos, Othon
- Stephanopoulos, Gregory
- ORCID
- Venue
- Nature
- Published
- 2011-11-20
- Volume
- 481
- Issue
- 7381
- Pages
- 380-384
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3710581
- OpenAlex
- W2116516144
- Cited by
- 1,791
- References
- 43
- Citations by year
- 2026: 82 · 2025: 95 · 2024: 96 · 2023: 137 · 2022: 156 · 2021: 143 · 2020: 149 · 2019: 125 · 2018: 100 · 2017: 135 · 2016: 129 · 2015: 125 · 2014: 119 · 2013: 112 · 2012: 84
- FWCI
- 34.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- RePEc: Research Papers in Economics (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation
- Wellcome Trust
- Agios Pharmaceuticals
- National Institutes of Health
- National Cancer Institute (R01CA160458, R01CA122591, P30CA014051)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075850)
- 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 › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- IDH1, lipogenesis, hypoxia, reductive carboxylation, alpha-ketoglutarate, acetyl-CoA, fatty acid synthesis, VHL, renal cell carcinoma, cancer metabolism, mitochondrial dysfunction, aerobic glycolysis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Acetyl Coenzyme A, Carbon, Carcinoma, Renal Cell, Cells, Cultured, Citric Acid Cycle, Glutamine, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Kidney Neoplasms, Oxidation-Reduction, Oxygen, Cell Hypoxia, CD8-Positive T-Lymphocytes, Palmitic Acid, Cell Line, Tumor, Lipogenesis, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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