Mitochondrial dysfunction in pulmonary hypertension

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- adenosylmethionine (SAM) binding to mRNA, which could be responsible for NFU1 insufficiency in the absence of its mutation.