TY - JOUR
T1 - Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway
AU - Ducker, Gregory S.
AU - Chen, Li
AU - Morscher, Raphael J.
AU - Ghergurovich, Jonathan M.
AU - Esposito, Mark
AU - Teng, Xin
AU - Kang, Yibin
AU - Rabinowitz, Joshua D.
N1 - Funding Information:
We thank all members of the J.D.R. lab, and, in particular, W. Lu, S. Zhang, and Z. Zhang for assistance in mass spectrometry methods and X. Su for isotope correction calculations. We thank C. Lewis for the IDH reporter construct. We acknowledge V. Suri and M. Manfredi of Raze Therapeutics for assistance with tumor-growth data. This research was supported in part by funding to J.D.R. from the US National Institutes of Health (NIH) ( R01CA16359-01A1 ) and Stand Up to Cancer ( SU2C-AACR-DT0509 ) and to Y.K. from the Brewster Foundation , the NIH ( R01CA141062 ), and the US Department of Defense ( BC123187 ). G.S.D. is supported by a postdoctoral fellowship ( PF-15-190-01- TBE ) from the American Cancer Society and received prior assistance from an NJCCR postdoctoral fellowship ( DFHS15PPC044 ). M.E. is supported by a predoctoral fellowship from the NIH ( F31CA192461 ). R.J.M. is supported by a PMU-FFF fellowship ( L-15/03/004-MOR ). J.D.R. is a founder and member of the scientific advisory board of Raze Therapeutics, which seeks to target 1C metabolism for cancer therapy.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/14
Y1 - 2016/6/14
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2016.04.016
DO - 10.1016/j.cmet.2016.04.016
M3 - Article
C2 - 27211901
AN - SCOPUS:84975455372
SN - 1550-4131
VL - 23
SP - 1140
EP - 1153
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -