We propose that a bifurcation in mitochondrial one-carbon metabolism is a key control mechanism in determining the fate of one-carbon units, to formate or CO2. During cobalamin deficiency in rats the disposition of 10-formyl-tetrahydrofolate carbon is shifted in favor of formate production. This may represent a mechanism to generate more one-carbon units for the replenishment of the S-adenosylmethionine pool which is depleted in this condition.
Background Formate can be incorporated into 10-formyl-tetrahydrofolate (10-formyl-THF), which is a substrate for purine synthesis, and after further reduction of the one-carbon group, may be used as a substrate for thymidylate synthesis and for homocysteine remethylation. Objective We examined plasma formate concentrations and the expression of genes involved in the production and utilization of formate in fetal and neonatal rats and in pregnant and virgin female rats. Methods In 1 experiment, plasma formate was measured by GC-MS in rats aged 1–56 d. In a second experiment, virgin female (adult) rats, 19-d pregnant rats (P) and their male and female fetuses (F), and 3-d-old (N) and 7-d-old (J) offspring had plasma and amniotic fluid analyzed for formate by GC-MS, mRNA abundance in liver and placenta by qPCR, and several plasma amino acids by HPLC. Results The plasma formate concentration was significantly higher in fetuses at embryonic day 19 than in the mothers. It was also significantly higher in neonatal rats but slowly returned to adult concentrations by ∼3 wk. The abundance of mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase (Mthfd1l) mRNA was significantly higher in placenta (PP) and F liver than in liver of N or J. Expression of mitochondrial bifunctional NAD-dependent methylene-tetrahydrofolate dehydrogenase/methenyl-tetrahydrofolate cyclohydrolase (Mthfd2) was significantly enriched in PP and liver of P, intermediate in F liver, and much lower in liver of N and J, relative to PP. Serine hydroxymethyltransferase 2 (Shmt2), methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), and glycine decarboxylase protein of the glycine cleavage system (Gldc) mRNA expression was significantly lower in PP compared with other groups. Cytoplasmic NAD(P)-dependent 10-formyl-tetrahydrofolate dehydrogenase (Aldh1/1) and mitochondrial NAD(P)-dependent 10-formyl-tetrahydrofolate dehydrogenase (Aldh1/2) , genes responsible for the catabolism of 10-formylTHF, were very weakly expressed in PP, low in livers of F and N, and reached the significantly higher adult levels in J. Serine, glycine, and methionine concentrations in plasma of F were significantly higher than in plasma of P. Conclusions Formate metabolism is highly active in fetuses and in placenta of pregnant rats.
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