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

TitleReversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway.
Publication TypeJournal Article
Year of Publication2016
AuthorsDucker, GS, Chen, L, Morscher, RJ, Ghergurovich, JM, Esposito, M, Teng, X, Kang, Y, Rabinowitz, JD
JournalCell Metab
Volume23
Issue6
Pagination1140-1153
Date Published2016 06 14
ISSN1932-7420
KeywordsAminoimidazole Carboxamide, Carbon, Cell Compartmentation, Cell Proliferation, Colonic Neoplasms, CRISPR-Cas Systems, Cytosol, Folic Acid, Formates, Gene Knockout Techniques, Gene Library, Glycine, Glycine Hydroxymethyltransferase, HCT116 Cells, HEK293 Cells, Humans, Leucovorin, Metabolic Networks and Pathways, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Mutation, NADP, Ribonucleotides, Serine, Xenograft Model Antitumor Assays
Abstract

<p>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.</p>

DOI10.1016/j.cmet.2016.04.016
Alternate JournalCell Metab.
PubMed ID27211901
PubMed Central IDPMC4909566
Grant ListF32 GM119195 / GM / NIGMS NIH HHS / United States
R01 CA141062 / CA / NCI NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
F31 CA192461 / CA / NCI NIH HHS / United States
P30 CA016359 / CA / NCI NIH HHS / United States
T32 HG003284 / HG / NHGRI NIH HHS / United States