ENDOTHELIAL FRATAXIN DEFICIENCY DRIVES NUCLEAR REPLICATION STRESS-INDUCED SENESCENCE AND MITOCHONDRIAL DYSFUNCTION ACROSS MULTIPLE SUBTYPES OF PULMONARY HYPERTENSION

Miranda K. Culley, Jingsi Zhao, Ying Tang, Yi Yin Tai, Dror Perk, Vinny Negi, Yen-Chun Lai, Qiujun Yu, Adam Handen, Gil Speyer, Seungchan Kim, Taijyu Satoh, Michael Reynolds, Sruti Shiva, Annie Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Karen Norris, Aditi Gurkar, Mingxia Gu, Marlene Rabinovitch, Thomas Bertero and Stephen Chan; Journal of the American College of Cardiology, Volume 75, Issue 11 Supplement 1, March 2020 DOI: 10.1016/S0735-1097(20)34284-4

Endothelial DNA damage and metabolic dysfunction are linked to pulmonary hypertension (PH). Their joint regulation, control of cellular senescence, and relevance across PH subtypes are unknown. Mutations in the iron-sulfur (Fe-S) biogenesis gene frataxin (FXN) disrupt DNA integrity and metabolism, causing Friedreich’s ataxia (FRDA) and hypertrophic cardiomyopathy, often complicated by PH. Because Fe-S loss promotes PH, we hypothesized endothelial FXN deficiency induces genotoxic and metabolic dysregulation and predisposes to PH, particularly vascular remodeling due to ventricular stiffening.

FXN deficiency promotes replication stress-induced senescence and metabolic reprogramming across PH subtypes, including a predisposition to PH in FRDA. Our data endorse developing PH diagnostics and therapeutics related to Fe-S biology and genotoxic stress, namely for PH due to left heart disease.