Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and Impairs Hepatocellular Tumorigenesis.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Cambridge, MA] : Cell Press, c 2012-
    • Subject Terms:
      Citric Acid Cycle*; Carcinogenesis/*metabolism ; Carcinoma, Hepatocellular/*metabolism ; Glutamine/*metabolism ; Glutathione/*biosynthesis ; Liver Neoplasms/*metabolism ; Mitochondria/*metabolism ; Pyruvic Acid/*metabolism; Animals ; Apoptosis ; Carcinoma, Hepatocellular/genetics ; Cell Line, Tumor ; Hepatocytes/metabolism ; Humans ; Liver Neoplasms/genetics ; Mice, Inbred C57BL ; Neoplasm Proteins/metabolism ; Organ Specificity ; Transcriptome/genetics
    • Abstract:
      Hepatocellular carcinoma (HCC) is a devastating cancer increasingly caused by non-alcoholic fatty liver disease (NAFLD). Disrupting the liver Mitochondrial Pyruvate Carrier (MPC) in mice attenuates NAFLD. Thus, we considered whether liver MPC disruption also prevents HCC. Here, we use the N-nitrosodiethylamine plus carbon tetrachloride model of HCC development to test how liver-specific MPC knock out affects hepatocellular tumorigenesis. Our data show that liver MPC ablation markedly decreases tumorigenesis and that MPC-deficient tumors transcriptomically downregulate glutathione metabolism. We observe that MPC disruption and glutathione depletion in cultured hepatomas are synthetically lethal. Stable isotope tracing shows that hepatocyte MPC disruption reroutes glutamine from glutathione synthesis into the tricarboxylic acid (TCA) cycle. These results support a model where inducing metabolic competition for glutamine by MPC disruption impairs hepatocellular tumorigenesis by limiting glutathione synthesis. These findings raise the possibility that combining MPC disruption and glutathione stress may be therapeutically useful in HCC and additional cancers.
      (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      T32 GM007337 United States GM NIGMS NIH HHS; F31 NS106773 United States NS NINDS NIH HHS; P30 CA086862 United States CA NCI NIH HHS; T32 HL007344 United States HL NHLBI NIH HHS; T32 HL007638 United States HL NHLBI NIH HHS; F32 DK116522 United States DK NIDDK NIH HHS; F32 DK101183 United States DK NIDDK NIH HHS; R01 CA132962 United States CA NCI NIH HHS; R01 DK104998 United States DK NIDDK NIH HHS; T32 DK112751 United States DK NIDDK NIH HHS; R01 CA182804 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Mitochondrial Pyruvate Carrier; cancer; glutamine; glutathione; hepatocellular carcinoma; liver; metabolomics; stable isotope tracing; synthetic lethality
    • Accession Number:
      0 (Neoplasm Proteins)
      0RH81L854J (Glutamine)
      8558G7RUTR (Pyruvic Acid)
      GAN16C9B8O (Glutathione)
    • Publication Date:
      Date Created: 20190905 Date Completed: 20200914 Latest Revision: 20200914
    • Publication Date:
      20231215
    • Accession Number:
      PMC6746334
    • Accession Number:
      10.1016/j.celrep.2019.07.098
    • Accession Number:
      31484072