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.
Tuesday, August 23, 2022
Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function
Miranda K Culley, Monica Mehta, Jingsi Zhao, Dror Perk, Yi Yin Tai, Ying Tang, Sruti Shiva, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero, Stephen Y Chan; bioRxiv 2022.08.22.504849; doi:org/10.1101/2022.08.22.504849
