Pulmonary hypertension in rats with human mutation of NFU1 is oxygen sensitive

Mitochondrial dysfunction is known to be directly associated with the pathogenesis of pulmonary hypertension (PH). NFU1 is an important mitochondrial protein involved in [4Fe-4S] cluster biogenesis and incorporation of newly synthesized [4Fe-4S] clusters into the target proteins. Patients with autosome recessive inheritance of NFU1 mutation c.622Gu003eT have the reduced activity of respiratory chain complex II, lipoic-acid dependent enzymes and develop pulmonary hypertension (PH) in ~ 70% of cases. In this study, we analyzed the genetic rat model that reproduces the human mutation of NFU1. The penetrance of pulmonary hypertension in homozygote NFU1 G206C rats was found to be 73% in females and only 22% in males. Both genders showed a significantly reduced complex II and PHD activity. However, while in females the expression of both complex II subunits (SDHA and SDHB) was significantly impaired, males showed a decreased expression of SDHA only. The limited development of PH in males also correlated with an increased expression of another Fe-S scaffold protein, ISCU. This protection was not evident in female rats. The previous research showed a critical role of NFU1 in the protection of [4Fe-4S] clusters against oxidation. The inhibition of complex II in NFU1 knockouts occurred only in the presence of oxygen (in normoxia) but not in anoxia. We confirmed that exposure to hypoxia protected NFU1 G206C rats compared to wild type. This discovery may highlight the mechanisms responsible for PH development in humans that are not exposed to hypoxic conditions. We conclude that in normoxic conditions human mutation of NFU1 reproduced in healthy rats is sufficient to induce PH and replicate the gender dimorphism seen in humans. In the presence of oxygen mitochondrial dysfunction due to NFU1 insufficiency gets synergistically potentiated by the oxidative stress.