Metabotype analysis of Mthfd1l-null mouse embryos using desorption electrospray ionization mass spectrometry imaging
- 8 April 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Analytical and Bioanalytical Chemistry
- Vol. 413 (13), 3573-3582
- https://doi.org/10.1007/s00216-021-03308-5
Abstract
Mammalian folate-dependent one-carbon (1C) metabolism provides the building blocks essential during development via amino acid interconversion, methyl-donor production, regeneration of redox factors, and de novo purine and thymidylate synthesis. Folate supplementation prevents many neural tube defects (NTDs) that occur during the embryonic process of neurulation. The mechanism by which folate functions during neurulation is not well understood, and not all NTDs are preventable by folate supplementation. Mthfd1l is a mitochondrial 1C metabolism enzyme that produces formate, a 1C donor that fuels biosynthesis and the methyl cycle in the cytoplasm. Homozygous deletion of the Mthfd1l gene in mice (Mthfd1lz/z) causes embryonic lethality, developmental delay, and folate-resistant NTDs. These mice also have defects in cranial mesenchyme formation. In this work, mass spectrometry imaging was used to obtain ion maps of the cranial mesenchyme that identified the spatial distribution and relative abundance of metabolites in wild-type and Mthfd1lz/z embryos. The relative abundances of purine and thymidylate derivatives, as well as amino acids, were diminished in the cranial mesenchyme of Mthfd1lz/z embryos. Loss of Mthfd1l activity in this region also led to abnormal levels of methionine and dysregulated energy metabolism. These alterations in metabolism suggest possible approaches to preventing NTDs in humans. Graphical abstractKeywords
Funding Information
- Welch Foundation (F-1895)
- National Institutes of Health (HD083809)
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