Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension. Issue 6 (30th March 2015)

• Record Type: Journal Article
• Authors: 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;
• Is Part Of: EMBO molecular medicine. Volume 7:Issue 6(2015:Jun.)
• Page Start: 695
• Page End: 713
• Publication Date: 2015-03-30
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201404511
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201404511-abs-0001"> <title>Abstract</title> <p>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 <italic>in vivo</italic> 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 <italic>ISCU</italic> 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.</p> </abstract>