Dataset Information

A single mutation in NFU1 gene metabolically reprograms pulmonary artery smooth muscle cells

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Pulmonary Hypertension

SUBMITTER: Paul Langlais

LAB HEAD: Paul Langlais

PROVIDER: PXD015022 | Pride | 2021-09-08

REPOSITORIES: Pride

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	20181026_R2D2_4148_1.raw	Raw
	20181026_R2D2_4148_1.raw (F005578).mzid_20181026_R2D2_4148_1.raw_(F005578).pride.mgf.gz	Mzid
	20181026_R2D2_4148_1.raw (F005578).pride.mztab.gz	Mztab
	20181026_R2D2_4148_1.rawF005578.mzid.gz	Mzid
	20181026_R2D2_4148_1.rawF005578.mzid_20181026_R2D2_4148_1.raw_F005578.MGF	Mzid

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Publications

Single Mutation in the <i>NFU1</i> Gene Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells.

James Joel J Zemskova Marina M Eccles Cody A CA Varghese Mathews V MV Niihori Maki M Barker Natalie K NK Luo Moulun M Mandarino Lawrence J LJ Langlais Paul R PR Rafikova Olga O Rafikov Ruslan R

Arteriosclerosis, thrombosis, and vascular biology 20201210 2

<h4>Objective</h4>NFU1 is a mitochondrial iron-sulfur scaffold protein, involved in iron-sulfur assembly and transfer to complex II and LAS (lipoic acid synthase). Patients with the point mutation NFU1<sup>G208C</sup> and CRISPR/CAS9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9)-generated rats develop mitochondrial dysfunction leading to pulmonary arterial hypertension. However, the mechanistic understanding of p ...[more]

PMID: 33297749

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Project description:Abstract: Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included tfam (−0.45-fold), suggesting impaired mitochondrial biogenesis, Cyp2e1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (Dhrs7c) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (Galnt13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (Postn; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (Ltbp2), thrombospondin4 (Thbs4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, Annexin A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.