In patients with Friedreich ataxia (FA) pulmonary hypertension (PH) may represent a previously underappreciated clinical phenotype, according to findings from a study published in Vascular Pharmacology.

Robust pulmonary vascular remodeling is observed among patients with FA—a disorder that is characterized by the presence of cardiomyopathy and severe neurodegeneration. It is well known that FA is caused by trinucleotide repeat mutations in the frataxin (FXN) gene. Such tissue-specific phenotypes have traditionally been attributed to oxidative stress and mitochondrial reprogramming.

Recognizing that mitochondrial dysfunction is a well-accepted driver of pulmonary vascular disease and of endothelial dysfunction in particular, the researchers sought to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose individuals to PH.

Although iron-sulfur (Fe-S)-specific metabolic changes promote pathologic alterations in pulmonary artery endothelial cells, which is consistent with the development of PH, whether deficiency in FXN controls endothelial metabolic and resultant pathophenotypic reprogramming remains to be elucidated.

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To generate endothelial-specific knockout of FXN, the researchers crossed FXN flox/flox mice with
Cdh5(PAC)-CreERT2 mice. At 10 weeks, the mice were given 30 mg of tamoxifen for 3 consecutive days. After 2 weeks had elapsed, the mice were exposed to conditions of hypoxia (ie, an oxygen level of 10%) for the next 3 weeks. Following this, their lung tissue was harvested for examination.

Results of the analysis reported the following findings:

  • Acquired FXN deficiency disrupted Fe-S-dependent mitochondrial metabolism and respiration;
  • FXN deficiency generated pulmonary artery endothelial dysfunction;
  • Genetic FXN deficiency mirrored the metabolic dysfunction that triggers endothelial metabolic dysfunction; and
  • Endothelial FXN deficiency drove the dysregulation of endothelial vasomotor mediators in vivo.

In fact, loss of endothelial FXN was associated with an imbalance in pulmonary vasomotor tone mediators in vivo and in vitro, which is a process that contributes, to some degree, to the overall expressions of PH.

The data reported herein were observed in primary pulmonary endothelial cells following pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells obtained from patients with FXN mutations.

“Altogether, this study indicates [that] FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability,” the researchers explained. “Our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency,” they concluded.


Culley MK, Rao RJ, Mehta M, et al. Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function. Vascul Pharmacol. Published online May 8, 2023. doi:10.1016/j.vph.2023.107181