Flexibility of systemic one-carbon metabolism partially buffers dietary methyl donor deficiency

Summary Choline is a methyl-rich nutrient used in lipid synthesis and catabolized to support one-carbon metabolism. Choline consumption in most humans remains less than the suggested adequate intake, yet how systemic metabolism compensates for choline deficiency is not fully described. Here, we use in vivo stable isotope tracing to explore the fate of choline in mammalian tissues. We find that choline is catabolized in the liver to support both the methionine cycle and the mitochondrial folate cycle in addition to its role in lipid synthesis. When dietary methyl donors are deficient, surprisingly, we find maintained systemic choline and methionine fluxes, but diminished contribution of choline to the folate cycle. To compensate for dietary methyl deficiency, systemic flux of serine is doubled by increased kidney synthesis which supplies one-carbon units for increased methionine synthesis in the liver. Our study suggests that systemic one-carbon flexibility can compensate for nutritional methyl deficiency by inter-organ nutrient exchange.