Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
By Christian M. Metallo, P. Gameiro, Eric L. Bell, Katherine R. Mattaini, Juanjuan Yang, Karsten Hiller, C. Jewell, Zachary R. Johnson, D. Irvine, L. Guarente and 4 more. Nature, 2011
1,766 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/885e8428cbf44420aac2f2f53e79b51784530d2e
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In Cancer Research
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In Molecular Biology
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Citations in the corpus
- Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Under hypoxic conditions, several cell lines utilize glutamine carbon as the major source of de novo lipogenesis through the reductive carboxylation of glutamine-derived αKG (153, 154).”
- ROS homeostasis and metabolism: a dangerous liason in cancer cells (2016, background): “Interestingly, tumors with impaired TCA cycle activity (or mutations in the mETC complexes) and that rely on glycolysis for ATP synthesis, shift to reductive glutaminolysis to mediate biosynthetic processes and cell survival.(137,138) Such tumor cells depend on mitochondrial-derived ROS to promote c”
- An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis (2015, background): “In cells with ETC dysfunction, glutamine is a major source of citrate through the “reductive carboxylation” pathway (Metallo et al., 2012; Mullen et al., 2012).”
- Metabolomics and isotope tracing (2018, background): “In contrast, reductive carboxylation of a-ketoglutarate produces M+5 citrate (Yoo et al., 2008; Mullen et al., 2011; Metallo et al., 2011).”