Mammalian MTHFD2L Encodes a Mitochondrial Methylenetetrahydrofolate Dehydrogenase Isozyme Expressed in Adult Tissues

• Published in: The Journal of biological chemistry Vol. 286; no. 7; pp. 5166 - 5174
• Main Authors: Bolusani, Swetha, Young, Blake A., Cole, Nicola A., Tibbetts, Anne S., Momb, Jessica, Bryant, Joshua D., Solmonson, Ashley, Appling, Dean R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.02.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Alternative Splicing - physiology; Animals; Cell Metabolism; CHO Cells; Cricetinae; Cricetulus; Folate Metabolism; Gene Expression Regulation, Enzymologic - physiology; Gene Structure; Humans; Isoenzymes - biosynthesis; Isoenzymes - genetics; Membrane Enzymes; Metabolism; Methylenetetrahydrofolate Dehydrogenase (NADP) - biosynthesis; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Mitochondria - enzymology; Mitochondria - genetics; Mitochondrial Metabolism; Mitochondrial Proteins - biosynthesis; Mitochondrial Proteins - genetics; One-carbon Metabolism; Organ Specificity - physiology; Rats; Rats, Sprague-Dawley; Tetrahydrofolates - metabolism; Gene Structure; One-carbon Metabolism; Membrane Enzymes; Cell Metabolism; Folate Metabolism; Mitochondrial Metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.196840

Previous studies in our laboratory showed that isolated, intact adult rat liver mitochondria are able to oxidize the 3-carbon of serine and the N-methyl carbon of sarcosine to formate without the addition of any other cofactors or substrates. Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH2-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH2-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified. The recombinant protein exhibits robust NADP+-dependent CH2-THF dehydrogenase activity when expressed in yeast. The enzyme is localized to mitochondria when expressed in CHO cells and behaves as a peripheral membrane protein, tightly associated with the matrix side of the mitochondrial inner membrane. The MTHFD2L gene is subject to alternative splicing and is expressed in adult tissues in humans and rodents. This CH2-THF dehydrogenase isozyme thus fills the remaining gap in the pathway from CH2-THF to formate in adult mammalian mitochondria.