ArticleAmerican journal of respiratory cell and molecular biology2016
Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension.
Article in American journal of respiratory cell and molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 70 citations in OpenAlex.
- Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.Molecular cancer therapeutics · 2026Article
- Extracellular Hemoglobin, Hypoxia, and Macrophage-Mediated Pulmonary Vascular Remodeling in Hemolytic Disease.International journal of molecular sciences · 2026Review
- Lactylation modification: a new bridge connecting macrophage metabolism and pulmonary hypertension.Applied microbiology and biotechnology · 2026Review
- Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.Genes & diseases · 2026Review
- Adventitial Niches, Complement and Inflammation in Pulmonary Vascular Disease: Current Status and Future Directions.Comprehensive Physiology · 2026Review
- Beyond the Vasculature: The Emerging Role of Systemic Metabolism and Immunometabolism in Pulmonary Arterial Hypertension.International journal of molecular sciences · 2026Review
- High-Throughput Metabolomics in Transfusion Medicine.Methods in molecular biology (Clifton, N.J.) · 2026Article
- c-Myc promotes metabolic reprogramming in pulmonary hypertension via the stimulation of glutaminolysis and the reductive tricarboxylic acid cycle.Redox biology · 2025Article
- Enhanced lung endothelial glycolysis is implicated in the development of severe pulmonary hypertension in type 2 diabetes.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Exploring the interplay between mitochondria and endoplasmic reticulum in pulmonary arterial hypertension.Frontiers in cardiovascular medicine · 2025Review
- Epigenetic and Metabolic Reprogramming of Fibroblasts in Crohn's Disease Strictures Reveals Histone Deacetylases as Therapeutic Targets.Journal of Crohn's & colitis · 2024Article
- Unveiling the metabolic landscape of pulmonary hypertension: insights from metabolomics.Respiratory research · 2024Review
- Review
- SIRT3 Is a Critical Regulator of Mitochondrial Function of Fibroblasts in Pulmonary Hypertension.American journal of respiratory cell and molecular biology · 2023Article
- Boosting the Exhausted Vasculature-SIRT3 (to the) Rescue.American journal of respiratory cell and molecular biology · 2023Article
- The Effect of Hypoxia-inducible Factor Inhibition on the Phenotype of Fibroblasts in Human and Bovine Pulmonary Hypertension.American journal of respiratory cell and molecular biology · 2023Article
- Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension.Vascular pharmacology · 2023Article
- Mitochondria in hypoxic pulmonary hypertension, roles and the potential targets.Frontiers in physiology · 2023Review
- Mitochondrial dynamics in vascular remodeling and target-organ damage.Frontiers in cardiovascular medicine · 2023Review
- Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease.British journal of haematology · 2022Article
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Authors and funding
11 authors at 5 institutions in 5 countries.
Funding
Abstract
Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.
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