PXD015022

PXD015022 is an original dataset announced via ProteomeXchange.

Title	A single mutation in NFU1 gene metabolically reprograms pulmonary artery smooth muscle cells
Description	NFU1 is an iron-sulfur (Fe-S) scaffold protein, involved in Fe-S assembly and transfer to a range of mitochondrial metalloproteins. Patients with the NFU1G208C mutation develop pulmonary arterial hypertension (PAH) with 70% penetrance. Rats with NFU1G206C homozygous mutation demonstrated the PAH phenotype showing increased pulmonary vasculature remodeling, right ventricular (RV) hypertrophy, and RV pressure. In the present study, we discovered phenotypic metabolic changes in pulmonary arterial smooth muscle cells (PASMC) from NFU1G206C homozygous mutant rats associated with alterations in the mitochondrial proteome. Quantitative analysis of the mitochondrial proteome showed significant changes in the abundance of 208 proteins involved in various metabolic and antioxidant functions in response to the NFU1 mutation. Our data indicates that the NFU1G206C homozygous mutant rats have decreased expression of complex I and II, which are known to depend on iron-sulfur clusters, and increased expression of complexes III to V, accompanied with a significant decrease in mitochondrial function, pyruvate dehydrogenase (PDH) activity and amplified glycolysis and anabolism in PASMC. The NFU1 mutation produced a dysregulated antioxidant system in the mitochondria which leads to increased levels of reactive oxygen species. Due to alterations in apoptosis regulating proteins, the NFU1G206C cells were found to exhibit high proliferation rates and resistance to apoptosis as compared with the wild type (WT). Finally, the NFU1G206C mitochondrial proteome showed significant abundance changes in proteins that regulate fatty acid (FA) metabolism and exhibited increased FA oxidation compared to WT, suggesting increased FA oxidation compensates for the decreased PDH activity. In conclusion, our data indicates that the NFU1G206C mutation induces a metabolic shift in the PASMC, which results in a hyper-proliferative and apoptosis resistant phenotype and presents a novel cellular model to study PAH.
HostingRepository	PRIDE
AnnounceDate	2021-09-08
AnnouncementXML	Submission_2021-09-08_14:18:20.302.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD015022
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Paul Langlais
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	Ammonia-loss; Phospho; Dehydrated; Oxidation; Acetyl; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-14 03:43:56	ID requested
⏵ 1	2021-09-08 14:18:21	announced

James J, Zemskova M, Eccles CA, Varghese MV, Niihori M, Barker NK, Luo M, Mandarino LJ, Langlais PR, Rafikova O, Rafikov R, Gene Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells. Arterioscler Thromb Vasc Biol, 41(2):734-754(2021) [pubmed]

submitter keyword: Liver, pulmonary arterial hypertension, NFU1, hyper-proliferative

Paul Langlais
contact affiliation	University of Arizona College of Medicine, Department of Medicine, Division of Endocrinology
contact email	langlais@deptofmed.arizona.edu
lab head
Paul Langlais
contact affiliation	University of Arizona
contact email	langlais@deptofmed.arizona.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015022
     1. Label: PRIDE project
     2. Name: A single mutation in NFU1 gene metabolically reprograms pulmonary artery smooth muscle cells