Deletion of the neural tube defect-associated gene Mthfd1l disrupts one-carbon and central energy metabolism in mouse embryos

The Journal of Biological Chemistry
Joshua D BryantD R Appling

Abstract

One-carbon (1C) metabolism is a universal folate-dependent pathway essential for de novo purine and thymidylate synthesis, amino acid interconversion, universal methyl-donor production, and regeneration of redox cofactors. Homozygous deletion of the 1C pathway gene Mthfd1l encoding methylenetetrahydrofolate dehydrogenase (NADP+-dependent) 1-like, which catalyzes mitochondrial formate production from 10-formyltetrahydrofolate, results in 100% penetrant embryonic neural tube defects (NTDs), underscoring the central role of mitochondrially derived formate in embryonic development and providing a mechanistic link between folate and NTDs. However, the specific metabolic processes that are perturbed by Mthfd1l deletion are not known. Here, we performed untargeted metabolomics on whole Mthfd1l-null and wildtype mouse embryos in combination with isotope tracer analysis in mouse embryonic fibroblast (MEF) cell lines to identify Mthfd1l deletion-induced disruptions in 1C metabolism, glycolysis, and the TCA cycle. We found that maternal formate supplementation largely corrects these disruptions in Mthfd1l-null embryos. Serine tracer experiments revealed that Mthfd1l-null MEFs have altered methionine synthesis, indicating that Mthfd1l dele...Continue Reading

References

May 4, 1993·Biochemistry·L F García-Martínez, D R Appling
Jul 27, 2000·Journal of Magnetic Resonance·U L GuntherH Ruterjans
Jun 28, 2002·The Journal of Biological Chemistry·Oliver E OwenRichard W Hanson
Dec 7, 2002·Behavior Genetics·Alexander A BachmanovMichael G Tordoff
Oct 16, 2003·American Journal of Physiology. Endocrinology and Metabolism·Steven R DavisJesse F Gregory
Aug 26, 2006·Birth Defects Research. Part A, Clinical and Molecular Teratology·Louisa P E DunlevyNicholas D E Greene
Jan 5, 2007·Nucleic Acids Research·David S WishartLori Querengesser
Jan 8, 2008·Cell Metabolism·Ralph J DeBerardinisCraig B Thompson
May 12, 2009·Nucleic Acids Research·Jianguo XiaDavid S Wishart
May 26, 2010·The Journal of Biological Chemistry·Natalia I KrupenkoSergey A Krupenko
Jul 22, 2010·Annual Review of Nutrition·Anne S Tibbetts, Dean R Appling
Jan 18, 2011·Chemico-biological Interactions·Kyle C StricklandSergey A Krupenko
Feb 25, 2011·The American Journal of Clinical Nutrition·Anna E BeaudinPatrick J Stover
Jun 3, 2011·Current Protocols in Bioinformatics·Jianguo Xia, David S Wishart
Sep 15, 2011·BMC Bioinformatics·Christian Ludwig, Ulrich L Günther
Dec 26, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jessica MombDean R Appling
Dec 19, 2013·PloS One·Stefano TizianiGiovanni Paternostro
Aug 15, 2014·Birth Defects Research. Part A, Clinical and Molecular Teratology·Alex HanslerSteven S Gross
May 24, 2016·Cell Metabolism·Gregory S DuckerJoshua D Rabinowitz
Jun 16, 2017·Scientific Reports·Xiyuan LuStefano Tiziani
Sep 26, 2017·American Journal of Medical Genetics. Part a·Kit Sing AuHope Northrup

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Citations

May 28, 2019·Human Molecular Genetics·Xiaoshan ZhouAnna Karlsson
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Nov 7, 2019·Current Opinion in Clinical Nutrition and Metabolic Care·John T Brosnan, Margaret E Brosnan
Aug 14, 2019·Molecular Metabolism·Matthias PietzkeAlexei Vazquez
Apr 9, 2021·Analytical and Bioanalytical Chemistry·Amanda VaughnDean R Appling
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Jul 13, 2020·Current Stem Cell Research & Therapy·Özlem Altundag, Betül Çelebi-Saltik

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