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

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.

• Authors: 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 Khan, Andrew 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
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 7 Issue 6 Pg. 695-713 (Jun 2015) ISSN: 1757-4684 [Electronic] England
• PMID: 25825391 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• ISCU protein, human
• Iron-Sulfur Proteins
• MIRN210 microRNA, human
• MicroRNAs
• Sulfur

Topics

• Animals
• Cells, Cultured
• Endothelial Cells (physiology)
• Female
• Genetic Predisposition to Disease
• Humans
• Hypertension, Pulmonary (etiology, genetics, pathology)
• Hypoxia (complications)
• Iron Deficiencies
• Iron-Sulfur Proteins (genetics)
• Mice
• MicroRNAs (genetics)
• Sulfur (deficiency)