Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism

Abstract

The recognition that mitochondria participate in folate-mediated one-carbon metabolism grew out of pioneering work beginning in the 1950s from the laboratories of D.M. Greenberg, C.G. Mackenzie, and G. Kikuchi. These studies revealed mitochondria as the site of oxidation of one-carbon donors such as serine, glycine, sarcosine, and dimethylglycine. Subsequent work from these laboratories and others demonstrated the participation of folate coenzymes and folate-dependent enzymes in these mitochondrial processes. Biochemical and molecular genetic approaches in the 1980s and 1990s identified many of the enzymes involved and revealed an interdependence of cytoplasmic and mitochondrial one-carbon metabolism. These studies led to the development of a model of eukaryotic one-carbon metabolism that comprises parallel cytosolic and mitochondrial pathways, connected by one-carbon donors such as serine, glycine, and formate. Sequencing of the human and other mammalian genomes has facilitated identification of the enzymes that participate in this intercompartmental one-carbon metabolism, and animal models are beginning to clarify the roles of the cytoplasmic and mitochondrial isozymes of these enzymes. Identifying the mitochondrial transporters for the one-carbon donors and elucidating how flux through these pathways is controlled are two areas ripe for exploration.

Mammalian Mitochondrial and Cytosolic Folylpolyglutamate Synthetase Maintain the Subcellular Compartmentalization of Folates

“…In contrast, the flux of 1-carbon units between the cytosol and mitochondria appears to be driven by the transport of serine, glycine, and formate across the mitochondrial membrane, consistent with the model of compartmentalized 1-carbon metabolism offered by Appling and colleagues (23,35,36). The complementation of deficiencies in mitochondrial FPGS and cytosolic FPGS by metabolites shown in Fig.…”

“…Ref. 23). We have questioned the functions for subcellular isoforms of FPGS and have directly studied the flux of folate polyglutamates across mitochondrial membranes in both directions, and the plasma membrane in the efflux direction using a doxycyclineinducible system that generated two cell lines that express the individual isoforms of FPGS at or near endogenous levels.…”

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

“…Folate-dependent one-carbon (1C) metabolism is highly compartmentalized in eukaryotes, and mitochondria play a critical role in cellular 1C metabolism (4). The cytoplasmic and mitochondrial compartments are metabolically connected by transport of 1C donors such as serine, glycine, and formate across the mitochondrial membranes, supporting a mostly unidirectional flow (clockwise in Fig.…”

“…It appears that under most conditions, the majority of 1C units for cytoplasmic processes are derived from mitochondrial formate (reviewed in ref. 4). This formate is exported to the cytoplasm where it is reattached to tetrahydrofolate (THF) for use in de novo purine biosynthesis, or further reduced for either thymidylate synthesis or remethylation of homocysteine to methionine.…”

Moonlighting Glutamate Formiminotransferases Can Functionally Replace 5-Formyltetrahydrofolate Cycloligase

“…The main reaction mediated by SHMT, the reversible conversion of serine to glycine and 5,10-methylene-THF, is a key source of C 1 units and SHMT is an almost ubiquitous enzyme (11)(12)(13). The capacity to form 5-CHO-THF is thus also almost universal, and consequently so is the need for 5-CHO-THF removal.…”