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This project contains all information pertaining to the replication of key experiments from this paper. It includes the detailed protocols, including reagents and author clarifications. We also include any comments from other contributors, researchers from the Science Exchange network, and further information with the original authors that we have learned since the beginning of the project. When experimental studies begin all data collected will also be deposited here, including data analysis and eventually the final written report. <br> **Original paper:** <br> 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. <a href="">Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.</a> Nature. 2012; Jan 19;481:380-4. doi: 10.1038/nature10602. <br> **Original abstract:**<br> 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 a-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 carboxyla- tion of glutamine-derived a-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.