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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)695-713
Number of pages19
JournalEMBO Molecular Medicine
Volume7
Issue number6
DOIs
Publication statusPublished - Jun 1 2015
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

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