Serine one-carbon catabolism with formate overflow.
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.
Cancer Research UK Beatson Institute, Glasgow, UK.
Johannes
0000-0002-9093-6210
J
Meiser
Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Sergey
0000-0002-0557-3153
S
Tumanov
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Oliver
O
Maddocks
Cancer Research UK Beatson Institute, Glasgow, UK.
Christiaan Fred
CF
Labuschagne
Cancer Research UK Beatson Institute, Glasgow, UK.
Dimitris
0000-0001-5298-7941
D
Athineos
Cancer Research UK Beatson Institute, Glasgow, UK.
Niels
N
Van Den Broek
Cancer Research UK Beatson Institute, Glasgow, UK.
Gillian M
GM
Mackay
Cancer Research UK Beatson Institute, Glasgow, UK.
Eyal
0000-0002-9770-0956
E
Gottlieb
Cancer Research UK Beatson Institute, Glasgow, UK.
Karen
K
Blyth
Cancer Research UK Beatson Institute, Glasgow, UK.
Karen
K
Vousden
Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Jurre J
JJ
Kamphorst
Cancer Research UK Beatson Institute, Glasgow, UK.
Alexei
A
Vazquez
Serine metabolism; folate metabolism; metformin; mitochondria metabolism; one-carbon metabolism; overflow metabolism