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

Research output: Contribution to journalArticle


  • Kevin White
  • Yu Lu
  • Sofia Annis
  • Andrew E. Hale
  • B. Nelson Chau
  • James E. Dahlman
  • Craig Hemann
  • Sara O. Vargas
  • Ivan Rosas
  • Mark A. Perrella
  • Juan C. Osorio
  • Kathleen J. Haley
  • Brian B. Graham
  • Rajan Saggar
  • Rajeev Saggar
  • W. Dean Wallace
  • David J. Ross
  • Omar F. Khan
  • Andrew Bader
  • Bernadette R. Gochuico
  • Majed Matar
  • Kevin Polach
  • Nicolai M. Johannessen
  • Haydn M. Prosser
  • Daniel G. Anderson
  • Robert Langer
  • Laurence A. Bindoff
  • David Systrom
  • Aaron B. Waxman
  • Richard C. Jin

External Institution(s)

  • Harvard University
  • Novartis
  • Regulus Therapeutics LLC
  • Translate Bio
  • Massachusetts Institute of Technology
  • Ohio State University
  • University of Colorado Denver
  • University of California at Los Angeles
  • University of Arizona
  • National Institutes of Health
  • Celsion-EGEN, Inc.
  • University of Bergen
  • Wellcome Sanger Institute


Original languageEnglish (US)
Pages (from-to)695-713
Number of pages19
JournalEMBO molecular medicine
Issue number6
StatusPublished - Jun 1 2015


Iron-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.

    Research areas

  • Endothelial, Iron-sulfur, Metabolism, MicroRNA, Mitochondria

Citation formats


White, K., Lu, Y., Annis, S., Hale, A. E., Chau, B. N., Dahlman, J. E., ... Chan, S. Y. (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.


White, K, Lu, Y, Annis, S, Hale, AE, Chau, BN, Dahlman, JE, Hemann, C, Opotowsky, AR, Vargas, SO, Rosas, I, Perrella, MA, Osorio, JC, Haley, KJ, Graham, BB, Kumar, R, Saggar, R, Saggar, R, Wallace, WD, Ross, DJ, Khan, OF, Bader, A, Gochuico, BR, Matar, M, Polach, K, Johannessen, NM, Prosser, HM, Anderson, DG, Langer, R, Zweier, JL, Bindoff, LA, Systrom, D, Waxman, AB, Jin, RC & Chan, SY 2015, 'Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension', EMBO molecular medicine, vol. 7, no. 6, pp. 695-713.