Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • November 29, 2018

Research

keywords

  • Carbon
  • Cytosol
  • Formates
  • Mitochondria
  • Neoplasms
  • Tetrahydrofolates

Identity

PubMed Central ID

  • PMC6568313

Scopus Document Identifier

  • 85056727052

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2018.09.041

PubMed ID

  • 30500537

Additional Document Info

volume

  • 175

issue

  • 6