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 particul...
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Springer Nature
2015-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404511 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kevin White |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2ba2fa97eac5474ab7e2db24f409a724 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-03-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-2ba2fa97eac5474ab7e2db24f409a7242025-08-20T04:02:56ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-03-017669571310.15252/emmm.201404511Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertensionKevin White0Yu Lu1Sofia Annis2Andrew E Hale3B Nelson Chau4James E Dahlman5Craig Hemann6Alexander R Opotowsky7Sara O Vargas8Ivan Rosas9Mark A Perrella10Juan C Osorio11Kathleen J Haley12Brian B Graham13Rahul Kumar14Rajan Saggar15Rajeev Saggar16W Dean Wallace17David J Ross18Omar F Khan19Andrew Bader20Bernadette R Gochuico21Majed Matar22Kevin Polach23Nicolai M Johannessen24Haydn M Prosser25Daniel G Anderson26Robert Langer27Jay L Zweier28Laurence A Bindoff29David Systrom30Aaron B Waxman31Richard C Jin32Stephen Y Chan33Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolRegulus TherapeuticsInstitute for Medical Engineering and Science, Massachusetts Institute of TechnologyThe Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State UniversityDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDepartment of Pathology, Boston Children's Hospital, Harvard Medical SchoolDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical SchoolDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical SchoolDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical SchoolDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical SchoolProgram in Translational Lung Research, University of ColoradoProgram in Translational Lung Research, University of ColoradoDepartments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Cardiothoracic Surgery, University of Arizona College of MedicineDepartments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los AngelesDepartments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los AngelesDepartment of Chemical Engineering, Massachusetts Institute of TechnologyInstitute for Medical Engineering and Science, Massachusetts Institute of TechnologyMedical Genetics Branch, National Human Genome Research Institute, National Institutes of HealthCelsion‐EGEN, Inc.Celsion‐EGEN, Inc.Department of Cardiology, University of BergenThe Wellcome Trust Sanger Institute, Wellcome Trust Genome CampusInstitute for Medical Engineering and Science, Massachusetts Institute of TechnologyInstitute for Medical Engineering and Science, Massachusetts Institute of TechnologyThe Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State UniversityDepartment of Clinical Medicine, University of BergenDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical SchoolDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical SchoolDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolAbstract 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.https://doi.org/10.15252/emmm.201404511endothelialiron–sulfurmetabolismmicroRNAmitochondria |
| spellingShingle | 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 Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension EMBO Molecular Medicine endothelial iron–sulfur metabolism microRNA mitochondria |
| title | Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension |
| title_full | Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension |
| title_fullStr | Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension |
| title_full_unstemmed | Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension |
| title_short | Genetic and hypoxic alterations of the microRNA‐210‐ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension |
| title_sort | genetic and hypoxic alterations of the microrna 210 iscu1 2 axis promote iron sulfur deficiency and pulmonary hypertension |
| topic | endothelial iron–sulfur metabolism microRNA mitochondria |
| url | https://doi.org/10.15252/emmm.201404511 |
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