Serine one-carbon catabolism with formate overflow

Johannes Meiser, Sergey Tumanov, Oliver Maddocks, Christiaan Fred Labuschagne, Dimitris Athineos, Niels Van Den Broek, Gillian M. Mackay, Eyal Gottlieb, Karen Blyth, Karen Vousden, Jurre J. Kamphorst, Alexei Vazquez*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

113 Citations (Scopus)

Abstract

Serine catabolism to glycine and a one-carbon unit has been linked to the anabolic requirements of proliferating mammalian cells. However, genome-scale modeling predicts a catabolic role with one-carbon release as formate. We experimentally prove that in cultured cancer cells and nontransformed fibroblasts, most of the serine-derived one-carbon units are released from cells as formate, and that formate release is dependent on mitochondrial reverse 10-CHO-THF synthetase activity. We also show that in cancer cells, formate release is coupled to mitochondrial complex I activity, whereas in nontransformed fibroblasts, it is partially insensitive to inhibition of complex I activity. We demonstrate that in mice, about 50% of plasma formate is derived from serine and that serine starvation or complex I inhibition reduces formate synthesis in vivo. These observations transform our understanding of one-carbon metabolism and have implications for the treatment of diabetes and cancer with complex I inhibitors.

Original languageEnglish
Article number1601273
JournalScience advances
Volume2
Issue number10
DOIs
Publication statusPublished - Oct 2016
Externally publishedYes

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