Mitochondrial formate dehydrogenase links mitochondrial and cytosolic one carbon metabolism via a one-carbon shunt

The transfer of one-carbon (C1) units is an integral part of cellular metabolism and is essential for the biosynthesis of nucleotides, amino acids, and cofactors, as well as for cellular methylation reactions. Within the plant cell, mitochondria are considered the hubs of one-carbon metabolism; however, the mechanisms and fluxes that distribute C1 units from the mitochondria throughout the cell are unknown. Formate, the anion of formic acid, is an intermediate of C1 metabolism and is converted to C1-tetrahydrofolate intermediates (C1 folates) or oxidized to CO2 by formate dehydrogenase. The presence of formate dehydrogenase in plant cells challenges the formate exchange between mitochondria and the cytosol, a basic principle of eukaryotic cellular and organellar C1 metabolism. Based on the biochemical and physiological characterization of Arabidopsis (Arabidopsis thaliana) formate dehydrogenase 1 (FDH1), we propose an FDH1-regulated C1 shunt linking mitochondrial and cytosolic C1 metabolism by formate exchange. Finally, we give a perspective on a cellular serine/formate shuttle that allows the distribution and transfer of C1 units according to the redox state within the compartments.