A new study has determined that deficiency of frataxin, mutations of which cause Friedrich ataxia (FA), predisposes patients to pulmonary hypertension via genotoxic iron-sulfur (Fe-S)-dependent genotoxic stress and senescence.

The study, presented at the 2023 American Thoracic Society International Conference in Washington, DC, this May, identified frataxin deficiency as a driver of pulmonary hypertension by rewiring endothelial metabolism and replication.

“Trinucleotide repeat mutations in the FXN gene cause Friedreich’s ataxia (FA), a disease characterized by cardiomyopathy and neurodegeneration,” the authors wrote. “Here, we aim to identify the mitochondria-specific effects of FXN (frataxin) deficiency in endothelium that predispose to pulmonary hypertension.”

FA is a hereditary autosomal-recessive condition affecting the cerebellar region of the brain, peripheral nerves, and spinal cord. It is caused by mutations in the FXN gene coding for frataxin, which controls ATP and iron homeostasis in mitochondria. The disease is characterized by muscle weakness, problems with walking and speech, and loss of proprioception and sensation.

Read more about FA comorbidities

The research team examined two cell types: pulmonary arterial endothelial cells with si-RNA knockdown of frataxin and inducible pluripotent stem cells from patients with FA differentiated into endothelial cells. Reverse transcriptase-qPCR, Seahorse analysis, Amplex Red colorimetric assay, ELISA, and scratch assay were performed.

They observed reduced mitochondrial respiration and increased glycolysis and oxidative species production in the frataxin knockdown cells. The cells from patients with FA presented a vasoconstrictive phenotype with decreased nitric oxide synthase and increased endothelin production, as seen in pulmonary hypertension.

The authors conclude that frataxin deficiency, either genetic or acquired, leads to pulmonary endothelium alterations combined with genotoxic stress and cell senescence, resulting in pulmonary hypertension. The findings are expected to contribute to the development of new diagnostic methods and treatment strategies for patients with this condition.


Mehta MP, Culley M, Zhao J, et al. Frataxin deficiency is a shared driver of endothelial metabolic dysfunction and senescence relevant to pulmonary hypertension. Presented at The 2023 ATS International Conference, Washington, DC, May 23, 2023. Abstract 405.