Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Name
Guarente_Reductive glutamine.pdf
Size
717.41 KB
Format
Adobe PDF
Checksum (MD5)
67ce07c1bc58f2ef0a356fd90c323519
Author(s)
Metallo, Christian M.
Gameiro, Paulo A.
Bell, Eric L.
Yang, Juanjuan
Hiller, Karsten
Jewell, Christopher M.
Vander Heiden, Matthew G.
Iliopoulos, Othon
Stephanopoulos, Gregory
Kelleher, Joanne Keene
Date Issued
November 2011
Journal
Nature
Publisher
Nature Publishing Group
Citation
Metallo, Christian M., Paulo A. Gameiro, Eric L. Bell, Katherine R. Mattaini, Juanjuan Yang, Karsten Hiller, Christopher M. Jewell, et al. “Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.” Nature (November 20, 2011).
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike 3.0
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/nature10602
