Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells exhibited a vasoconstrictive phenotype consistent with PH. These data were observed in both primary pulmonary endothelial cells after pharmacologic inhibition of FXN and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study defines FXN as a shared upstream driver of pathologic aberrations in both metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction, suggesting available and future therapies may be beneficial and targeted for PH subtypes with FXN deficiency.