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 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

doi:10.15252/emmm.201404511

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

EMBO Mol Med. 2015 Jun;7(6):695-713. doi: 10.15252/emmm.201404511.

Authors

Kevin White¹, Yu Lu¹, Sofia Annis¹, Andrew E Hale¹, B Nelson Chau², James E Dahlman³, Craig Hemann⁴, Alexander R Opotowsky⁵, Sara O Vargas⁶, Ivan Rosas⁷, Mark A Perrella⁸, Juan C Osorio⁷, Kathleen J Haley⁷, Brian B Graham⁹, Rahul Kumar⁹, Rajan Saggar¹⁰, Rajeev Saggar¹¹, W Dean Wallace¹⁰, David J Ross¹⁰, Omar F Khan¹², Andrew Bader¹³, Bernadette R Gochuico¹⁴, Majed Matar¹⁵, Kevin Polach¹⁵, Nicolai M Johannessen¹⁶, Haydn M Prosser¹⁷, Daniel G Anderson³, Robert Langer³, Jay L Zweier⁴, Laurence A Bindoff¹⁸, David Systrom⁷, Aaron B Waxman⁷, Richard C Jin¹, Stephen Y Chan¹⁹

Affiliations

¹ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Regulus Therapeutics, San Diego, CA, USA.
³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ The Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
⁵ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
¹⁰ Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Cardiothoracic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA.
¹² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Celsion-EGEN, Inc., Huntsville, AL, USA.
¹⁶ Department of Cardiology, University of Bergen, Bergen, Norway.
¹⁷ The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
¹⁸ Department of Clinical Medicine, University of Bergen, Bergen, Norway Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁹ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA sychan@partners.org.

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.

Keywords: endothelial; iron–sulfur; metabolism; microRNA; mitochondria.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding