Mitochondrial MTHFD2L Is a Dual Redox Cofactor-specific Methylenetetrahydrofolate Dehydrogenase/Methenyltetrahydrofolate Cyclohydrolase Expressed in Both Adult and Embryonic Tissues

• Published in: The Journal of biological chemistry 2014-05, Vol.289 (22), p.15507-15517
• Main Authors: Shin, Minhye, Bryant, Joshua D., Momb, Jessica, Appling, Dean R.
• Format: Article
• Language: English
• Subjects: Age Factors; Alternative Splicing - physiology; Aminohydrolases - genetics; Aminohydrolases - metabolism; Animals; Female; Folate Metabolism; Folic Acid - metabolism; Formate-Tetrahydrofolate Ligase - genetics; Formate-Tetrahydrofolate Ligase - metabolism; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Metabolism; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism; Mice; Mice, Inbred C57BL; Mitochondria - enzymology; Mitochondrial Metabolism; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Multifunctional Enzymes; NAD; NAD - metabolism; NADP - metabolism; Neural Tube - embryology; Neural Tube - enzymology; Neurodevelopment; Oxidation-Reduction; Pregnancy; Rats; Substrate Specificity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.555573

Mammalian mitochondria are able to produce formate from one-carbon donors such as serine, glycine, and sarcosine. This pathway relies on the mitochondrial pool of tetrahydrofolate (THF) and several folate-interconverting enzymes in the mitochondrial matrix. We recently identified MTHFD2L as the enzyme that catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. We show here that the MTHFD2L enzyme is bifunctional, possessing both CH2-THF dehydrogenase and 5,10-methenyl-THF cyclohydrolase activities. The dehydrogenase activity can use either NAD+ or NADP+ but requires both phosphate and Mg2+ when using NAD+. The NADP+-dependent dehydrogenase activity is inhibited by inorganic phosphate. MTHFD2L uses the mono- and polyglutamylated forms of CH2-THF with similar catalytic efficiencies. Expression of the MTHFD2L transcript is low in early mouse embryos but begins to increase at embryonic day 10.5 and remains elevated through birth. In adults, MTHFD2L is expressed in all tissues examined, with the highest levels observed in brain and lung. Mitochondria produce one-carbon units for cytoplasmic nucleotide and methyl group synthesis. MTHFD2L uses both NAD+ and NADP+ and is expressed in embryonic tissues during neural tube closure. This cofactor specificity allows for rapid response to changing metabolic conditions. These findings help explain why mammals possess two distinct mitochondrial isozymes that switch expression during neural tube closure.