# Mitochondrial dysfunction in pulmonary hypertension

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $664,270

## Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease with unmet medical need (1, 2). Extensive
basic, translational, and clinical research has provided strong evidence of impaired mitochondrial function in
PAH animals and patients (3-8). However, whether mitochondrial dysfunction (MD) plays a causative role or just
co-occurs in PAH remains unclear. Our research showed that MD induced by chronic inhibition of mitochondrial
electron transport chain (ETC) pharmacologically (9) or genetically (10) is sufficient to initiate PAH in otherwise
healthy rats. Nevertheless, the mechanisms that connect MD with PAH pathobiology are unidentified, preventing
the development of novel therapeutic options. Our team developed a rat model that reproduces severe MD
described in patients with a G208C point mutation in the NFU1 protein. Insufficiency of NFU1, which assembles
and transfers Fe-S clusters to mitochondrial proteins, severely impairs the activity of ETC complexes, lipoic acid
synthase (LAS), and pyruvate dehydrogenase (PDH) (4). These changes in mitochondrial function induce PAH
in 70% of NFU1 mutation carriers (4, 11). The same mutation reproduced in rats resulted in a similar MD
phenotype and initiated spontaneous PAH (10).
The detailed characterization of this new animal model revealed that MD induces several pathogenic events,
such as impaired angiogenesis, activated proliferative signaling, and altered lipid metabolism. While these events
are known as direct contributors to the pathobiology of PAH, the causative role of MD in their initiation has never
been defined. We found that NFU1 insufficiency with a subsequent loss of lipoic acid biosynthesis and impaired
oxidative phosphorylation played a key role in these pathogenic events. In addition, we uncovered the protective
role of mitoNEET, an outer mitochondrial Fe-S cluster protein and a critical metabolic switch in the pathogenesis
of cancers and diabetes but never studied in PAH. According to our preliminary data, RV cardiomyocytes (CMs)
isolated from NFU1 mutant rats have inhibited mitochondrial function and altered lipid homeostasis, while chronic
administration of mitoNEET ligand abolishes RV lipotoxicity and reverses RV hypertrophy. Based on our
comprehensive preliminary data, we hypothesize that impaired Fe-S cluster assembly due to NFU1 insufficiency
manifests as severe MD with decreased function of LAS, PDH, respiratory Complex II and metabolic regulator
mitoNEET, and leads to dysfunctional pulmonary angiogenesis, pulmonary artery remodeling, and altered RV
lipid homeostasis. These changes mediate an increase in pulmonary pressure and RV hypertrophy/dysfunction.
Given that expression of NFU1 was found to be significantly reduced in the lungs of idiopathic PAH (IPAH)
patients, we propose that MD induced by NFU1 insufficiency is relevant to the broader etiology of PAH. Indeed,
we discovered a novel mechanism of metabolic-based downregulation of NFU1 expression by S-
adenosylmethi...

## Key facts

- **NIH application ID:** 10897828
- **Project number:** 5R01HL160666-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Olga Rafikova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $664,270
- **Award type:** 5
- **Project period:** 2022-08-25 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897828

## Citation

> US National Institutes of Health, RePORTER application 10897828, Mitochondrial dysfunction in pulmonary hypertension (5R01HL160666-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10897828. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*