Characterization of the role of the mitochondrial one-carbon metabolism during embryonic development
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Neural tube defects (NTDs) are one of serious structural birth defects resulting from failure of neural tube closure. Folic acid supplementation is the essential factor for prevention of NTDs. Folate-dependent one-carbon metabolism is a central metabolic pathway participating in a diverse range of metabolic reactions. Mitochondrial one-carbon metabolism is crucial for production of formate as a major 1C donor to the cytoplasm and regeneration of redox cofactors. Mitochondrial MTHFD family enzymes, MTHFD2, MTHFD2L, and MTHFD1L, are major contributors for formate production in mammalian mitochondria. The MTHFD2 and MTHFD2L isozymes possess both CH₂-THF dehydrogenase and CH⁺-THF cyclohydrolase activities, catalyzing the reaction of 10-CHO-THF production in mitochondria. The dehydrogenase activity of these bifunctional enzymes can use either NAD⁺ or NADP⁺ with dual redox cofactor specificity, but requires both phosphate and Mg²⁺ when using NAD⁺. The NADP⁺-dependent dehydrogenase activity is inhibited by inorganic phosphate. With polyglutamylated THF substrate, both of MTHFD2 and MTHFD2L show higher NADP⁺-dependent activity than the monoglutamylated substrate. Phylogenetic analysis indicates that MTHFD2L may be evolved from invertebrate MTHFD2 which is homologous to a primitive fungal MTHFD1. MTHFD1L is expressed ubiquitously throughout the embryogenesis during neural tube closure, and significantly detected at the basal surface of the dorsal neuroepithelium. Lacking Mthfd1l causes retardation in growth and developmental progression. Mthfd1l knockout mouse embryos show defects in proliferation during late neural tube closure and head mesenchyme development during early neural tube closure. However, proliferation during early neural tube closure, apoptosis, and neural crest cell migration were not affected by the loss of Mthfd1l. Finally, we show that maternal formate supplementation significantly improves the dysregulated cellular processes in Mthfd1l [superscript z/z] embryos. This study elucidates the specific metabolic mechanisms underlying folate-associated birth defects, including NTDs.