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Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells.
Zheng, Yuxiang; Lin, Ting-Yu; Lee, Gina; Paddock, Marcia N; Momb, Jessica; Cheng, Zhe; Li, Qian; Fei, Dennis L; Stein, Benjamin D; Ramsamooj, Shivan; Zhang, Guoan; Blenis, John; Cantley, Lewis C.
Afiliación
  • Zheng Y; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Lin TY; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Lee G; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Paddock MN; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Momb J; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
  • Cheng Z; Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
  • Li Q; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Fei DL; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Stein BD; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Ramsamooj S; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Zhang G; Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
  • Blenis J; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • Cantley LC; Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: lcantley@med.cornell.edu.
Cell ; 175(6): 1546-1560.e17, 2018 11 29.
Article en En | MEDLINE | ID: mdl-30500537
Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carbono / Tetrahidrofolatos / Citosol / Formiatos / Mitocondrias / Neoplasias Límite: Humans Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carbono / Tetrahidrofolatos / Citosol / Formiatos / Mitocondrias / Neoplasias Límite: Humans Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos