Introduction: Mitochondrial dysfunction (MD) is known to be tightly associated with the pathobiology of pulmonary arterial hypertension (PAH). Recently, we discovered that rats reproducing a human mutation in NFU1 (NFU1 G206C ) have a severely altered mitochondrial function and spontaneously develop PAH characterized by increased right ventricle (RV) systolic pressure, RV hypertrophy, and severe obliterative disease of small pulmonary arteries. Hypothesis: In this study, we investigated whether MD induced by NFU1 mutation is sufficient to impair pulmonary angiogenesis contributing to PAH pathogenesis. Methods: Angiogenesis was assessed by micro-computed tomography of the pulmonary vasculature, microangiography of small pulmonary arteries (PAs), and histological evaluation of pulmonary capillary density. The angiogenic capacity was also investigated in vitro using cell migration and tube formation assays and analysis of EC tip cell population by flow cytometry. Results: MD significantly reduced the complexity of the pulmonary vascular network and prevented its further advancement (PA density (mean intensity/pxl) in WT vs. NFU1 G206C at 6 and 10 wks of age is 0.07±0.004 vs. 0.03±0.002 and 0.1±0.004 vs. 0.04±0.003; p<0.0001; N=5). NFU1 G206C rats had a reduced number of PA branches and junctions and impaired PA capillary density. PA endothelial cells isolated from NFU1 G206C rats demonstrated a strongly attenuated cell migration (~30% of WT) and tube formation capacity and a ~2.2 fold decrease in the number of CD-304 positive EC tip cells. Supplementation of NFU1 G206C rats with lipoic acid (LA, 1.70 mM in drinking water) aimed to attenuate the LA-synthase insufficiency secondary to NFU1 mutation, restored mitochondrial function, preserved the complexity of PA vascular network at WT level, and averted the PAH phenotype. Conclusions: We conclude that MD plays a causative role in the impaired pulmonary angiogenesis. Indeed, the lungs of NFU1 G206C rats fully reproduced the “dead-tree” picture of pulmonary vasculature described in PAH patients. At the same time, normalized mitochondrial function was sufficient to preserve pulmonary angiogenesis and prevent the PAH, suggesting the protective role of MD ameliorative approaches.