Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Gregory S. Ducker, Li Chen, Raphael J. Morscher, Jonathan M. Ghergurovich, Mark Esposito, Xin Teng, Yibin Kang, Joshua D. Rabinowitz

Research output: Contribution to journalArticlepeer-review

238 Scopus citations


One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here, we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-tetrahydrofolate (10-formyl-THF), and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis, with the mitochondrial pathway required in nutrient-poor conditions.

Original languageEnglish (US)
Pages (from-to)1140-1153
Number of pages14
JournalCell Metabolism
Issue number6
StatePublished - Jun 14 2016

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology


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