Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells
Bibli, Sofia Iris
Vasconez, Andrea Estefania
Oo, James A.
Romanoski, Casey E.
Lusis, Aldons J.
Leisegang, Matthias S.
Brandes, Ralf P.
AffiliationUniv Arizona, Dept Cellular & Mol Med
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationHitzel, J., Lee, E., Zhang, Y., Bibli, S. I., Li, X., Zukunft, S., ... & Oo, J. A. (2018). Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells. Nature communications, 9(1), 2292. https://doi.org/10.1038/s41467-018-04602-0
Rights© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractOxidized 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.
VersionFinal published version
SponsorsDFG Excellence Cluster "Cardiopulmonary System-ECCPS" [SFB 1039, IRTG1874/2, SFB 1118]; German Center for Cardiovascular Research DZHK; Faculty of Medicine, Goethe University, Frankfurt am Main, Germany; NIH [U01HG008451]; US National Institutes of Health [HL30568, HL095070]
- Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion.
- Authors: Koufaris C, Gallage S, Yang T, Lau CH, Valbuena GN, Keun HC
- Issue date: 2016 Aug 5
- Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase.
- Authors: Shin M, Momb J, Appling DR
- Issue date: 2017
- Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.
- Authors: Gustafsson R, Jemth AS, Gustafsson NM, Färnegårdh K, Loseva O, Wiita E, Bonagas N, Dahllund L, Llona-Minguez S, Häggblad M, Henriksson M, Andersson Y, Homan E, Helleday T, Stenmark P
- Issue date: 2017 Feb 15
- NAD- and NADP-dependent mitochondrially targeted methylenetetrahydrofolate dehydrogenase-cyclohydrolases can rescue mthfd2 null fibroblasts.
- Authors: Patel H, Di Pietro E, Mejia N, MacKenzie RE
- Issue date: 2005 Oct 1
- Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development.
- Authors: Tedeschi PM, Vazquez A, Kerrigan JE, Bertino JR
- Issue date: 2015 Oct