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

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

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