Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension

White, KevinLu, YuAnnis, SofiaHale, Andrew EChau, B NelsonDahlman, James EHemann, CraigOpotowsky, AlexanderVargas, SaraRosas, IvanPerrella, MarkOsorio, Juan CHaley, KathleenGraham, Brian BKumar, RahulSaggar, RajanSaggar, RajeevWallace, W DeanRoss, David JKhan, Omar FBader, AndrewGochuico, Bernadette RMatar, MajedPolach, KevinJohannessen, Nicolai MProsser, Haydn MAnderson, DanielLanger, RobertZweier, Jay LBindoff, Laurence ASystrom, DavidWaxman, AaronJin, Richard CChan, Stephen Y2015-07-132015White, K., Y. Lu, S. Annis, A. E. Hale, B. N. Chau, J. E. Dahlman, C. Hemann, et al. 2015. “Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension.” EMBO Molecular Medicine 7 (6): 695-713. doi:10.15252/emmm.201404511. http://dx.doi.org/10.15252/emmm.201404511.1757-4676http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295703Iron–sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.en-USendothelialiron–sulfurmetabolismmicroRNAmitochondriaGenetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertensionJournal Article2015-07-1310.15252/emmm.201404511