Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells

Nat Commun. 2018 Jun 12;9(1):2292. doi: 10.1038/s41467-018-04602-0.


Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Aminohydrolases / metabolism*
  • Animals
  • Aorta / cytology
  • Atherosclerosis / metabolism*
  • Bayes Theorem
  • Cardiovascular Diseases / metabolism
  • Endothelial Cells / metabolism*
  • Gene Expression Regulation
  • Genetic Techniques
  • Glycine / chemistry
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism*
  • Multifunctional Enzymes / metabolism*
  • Multigene Family
  • Neovascularization, Pathologic
  • Nucleotides / chemistry
  • Oxygen / chemistry
  • Phospholipids / chemistry*
  • Probability
  • Purines / chemistry
  • RNA, Small Interfering / metabolism
  • Zebrafish


  • Amino Acids
  • MTHFD2 protein, human
  • Multifunctional Enzymes
  • Nucleotides
  • Phospholipids
  • Purines
  • RNA, Small Interfering
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Aminohydrolases
  • Oxygen
  • Glycine