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

Author(s): Ducker, Gregory S; Chen, Li; Morscher, Raphael J; Ghergurovich, Jonathan M; Esposito, Mark; et al

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Abstract: 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. 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-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.
Publication Date: Jun-2016
Citation: Ducker, Gregory S, Chen, Li, Morscher, Raphael J, Ghergurovich, Jonathan M, Esposito, Mark, Teng, Xin, Kang, Yibin, Rabinowitz, Joshua D. (2016). Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway. Cell Metabolism, 23 (6), 1140 - 1153. doi:10.1016/j.cmet.2016.04.016
DOI: doi:10.1016/j.cmet.2016.04.016
ISSN: 1550-4131
Pages: 1140 - 1153
Type of Material: Journal Article
Journal/Proceeding Title: Cell Metabolism
Version: Author's manuscript

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