In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation
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Stephanopoulos_In vivo HIF.pdf
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Author(s)
Gameiro, Paulo A.
Yang, Juanjuan
Metelo, Ana M.
Baker, Rania
Wang, Zongwei
Arreola, Alexandra
Rathmell, W. Kimryn
Olumi, Aria F.
Stephanopoulos, Gregory
Iliopoulos, Othon
Date Issued
March 2013
Journal
Cell Metabolism
Publisher
Elsevier
Citation
Gameiro, Paulo A., Juanjuan Yang, Ana M. Metelo, Rocio Parez-Carro, Rania Baker, Zongwei Wang, Alexandra Arreola, et al. “In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation.” Cell Metabolism 17, no. 3 (March 2013): 372–385.
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Author's final manuscript
Abstract
Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [[superscript 1–13]C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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DOI of Published Version
https://doi.org/10.1016/j.cmet.2013.02.002
