Journal
EMBO MOLECULAR MEDICINE
Volume 7, Issue 6, Pages 695-713Publisher
WILEY
DOI: 10.15252/emmm.201404511
Keywords
endothelial; iron-sulfur; metabolism; microRNA; mitochondria
Categories
Funding
- NIH [K08HL096834, U54-CA151884, R01-DE016516-06, EB000244]
- McArthur-Radovsky Fund
- Lerner Fund
- Harris Fund
- Watkins Fund
- Gilead Research Scholars Fund
- Pulmonary Hypertension Association
- Intramural Research Program of the National Human Genome Research Institute
- Wellcome Trust [098051]
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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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