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

Hitzel J1,2, Lee E3,4, Zhang Y3,5, Bibli SI2,6, Li X7, Zukunft S2,6, Pflüger B1,2, Hu J2,6, Schürmann C1,2, Vasconez AE1,2, Oo JA1,2, Kratzer A8,9, Kumar S10, Rezende F1,2, Josipovic I1,2, Thomas D11, Giral H8,9, Schreiber Y12, Geisslinger G11,12, Fork C1,2, Yang X13, Sigala F14, Romanoski CE15, Kroll J7, Jo H10, Landmesser U8,9,16, Lusis AJ17, Namgaladze D18, Fleming I2,6, Leisegang MS1,2, Zhu J19,20, Brandes RP21,22
Source: Nat Commun.
Publication Date: ()
Issue: 9: 2292
Cells used in publication:
Endothelial, umbilical vein, human (HUVEC)
Species: human
Tissue Origin: vein
Endothelial, aortic, human (HAEC)
Species: human
Tissue Origin: aortic


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