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

Juliane Hitzel, Eunjee Lee, Yi Zhang, Sofia Iris Bibli, Xiaogang Li, Sven Zukunft, Beatrice Pflüger, Jiong Hu, Christoph Schürmann, Andrea Estefania Vasconez, James A. Oo, Adelheid Kratzer, Sandeep Kumar, Flávia Rezende, Ivana Josipovic, Dominique Thomas, Hector Giral, Yannick Schreiber, Gerd Geisslinger, Christian ForkXia Yang, Fragiska Sigala, Casey E. Romanoski, Jens Kroll, Hanjoong Jo, Ulf Landmesser, Aldons J. Lusis, Dmitry Namgaladze, Ingrid Fleming, Matthias S. Leisegang, Jun Zhu, Ralf P. Brandes

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number2292
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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