ArticleEMBO molecular medicine2015
Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension.
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Article in EMBO molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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95citing papers in PubMed
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Who cites it
95 citing papers in PubMed, 5 citations in OpenAlex.
- miR-210 locus deletion disrupts cellular homeostasis: an integrated genetic study.Scientific reports · 2025Article
- Therapeutic targets for pulmonary arterial hypertension: insights into the emerging landscape.Expert opinion on therapeutic targets · 2025Review
- MicroRNA-210 Mediates Hypoxic Pulmonary Hypertension in the Newborn Lamb.Hypertension (Dallas, Tex. : 1979) · 2025Article
- Pathophysiology of Group 3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxia.International journal of molecular sciences · 2025Review
- Decoding the enigmatic estrogen paradox in pulmonary hypertension: delving into estrogen metabolites and metabolic enzymes.Cellular & molecular biology letters · 2024Review
- MicroRNA-210 mediates hypoxia-induced pulmonary hypertension by targeting mitochondrial bioenergetics and mtROS flux.Acta physiologica (Oxford, England) · 2024Article
- Hypoxia-induced pulmonary hypertension in adults and newborns: implications for drug development.Drug discovery today · 2024Review
- miR-210 loss leads to widespread phenotypic and gene expression changes in human 293T cells.Frontiers in genetics · 2024Article
- Drug delivery systems for CRISPR-based genome editors.Nature reviews. Drug discovery · 2023Review
- Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function.Vascular pharmacology · 2023Article
- Targeting Mitochondrial Metabolic Dysfunction in Pulmonary Hypertension: Toward New Therapeutic Approaches?International journal of molecular sciences · 2023Review
- Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4-Human Leukocyte Antigen-DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension.Journal of the American Heart Association · 2023Article
- Therapeutic opportunities for senolysis in cardiovascular disease.The FEBS journal · 2023Review
- miR-roring Changes in Blood: miR-210 Reflects Hypoxic Disease Dynamics in Obstructive Sleep Apnea.American journal of respiratory and critical care medicine · 2023Article
- Obstructive Sleep Apnea-induced Endothelial Dysfunction Is Mediated by miR-210.American journal of respiratory and critical care medicine · 2023Article
- Mitochondria in hypoxic pulmonary hypertension, roles and the potential targets.Frontiers in physiology · 2023Review
- Iron Deficiency in Heart Failure and Pulmonary Hypertension.Current treatment options in cardiovascular medicine · 2022Article
- MicroRNA-210-mediated mtROS confer hypoxia-induced suppression of STOCs in ovine uterine arteries.British journal of pharmacology · 2022Article
- Mitochondrial Respiration in Peripheral Blood Mononuclear Cells Negatively Correlates with Disease Severity in Pulmonary Arterial Hypertension.Journal of clinical medicine · 2022Article
- MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction.Circulation · 2022Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
34 authors at 14 institutions in 3 countries.
Kevin WhiteDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Yu LuDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sofia AnnisDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Andrew E HaleDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
B Nelson ChauRegulus Therapeutics, San Diego, CA, USA.
James E DahlmanInstitute 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.
Craig HemannThe Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Alexander R OpotowskyDivisions 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.
Sara O VargasDepartment of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Ivan RosasDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Mark A PerrellaDivision 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.
Juan C OsorioDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Kathleen J HaleyDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Brian B GrahamProgram in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
Rahul KumarProgram in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
Rajan SaggarDepartments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Rajeev SaggarDepartment of Cardiothoracic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA.
W Dean WallaceDepartments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
David J RossDepartments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Omar F KhanDepartment 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.
Andrew BaderInstitute 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.
Bernadette R GochuicoMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Majed MatarCelsion-EGEN, Inc., Huntsville, AL, USA.
Kevin PolachCelsion-EGEN, Inc., Huntsville, AL, USA.
Nicolai M JohannessenDepartment of Cardiology, University of Bergen, Bergen, Norway.
Haydn M ProsserThe Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Daniel G AndersonInstitute 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.
Robert LangerInstitute 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.
Jay L ZweierThe Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Laurence A BindoffDepartment of Clinical Medicine, University of Bergen, Bergen, Norway Department of Neurology, Haukeland University Hospital, Bergen, Norway.
David SystromDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Aaron B WaxmanDivision of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Richard C JinDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Stephen Y ChanDivisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA sychan@partners.org.
Brigham and Women's Hospital · USHarvard University · USMassachusetts Institute of Technology · USUniversity of California, Los Angeles · USCelsion (United States) · USThe Ohio State University · USUniversity of Colorado Denver · USBoston Children's Hospital · USHaukeland University Hospital · NONational Institutes of Health · USRegulus Therapeutics (United States) · USUniversity of Arizona · USUniversity of Bergen · NOWellcome Sanger Institute · GB
Funding
The Development of Clinical Grade, Targeted Magnetic NanoparticlesU54CA151884 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI LANGER, ROBERT SAMUEL · 2010 to 2014
$11.3MCONTROLLED RELEASE OF MACROMOLECULESR01EB000244 · NIBIB · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI LANGER, ROBERT SAMUEL, TRAVERSO, CARLO GIOVANNI · 2002 to 2021
$6.1MIron-Sulfur Deficiency as a Critical Pathogenic Cause of Pulmonary HypertensionR01HL122596 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y · 2015 to 2024
$4.5MControlled Release of MacromoleculesR37EB000244 · NIBIB · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI LANGER, ROBERT SAMUEL · 2008 to 2017
$3.9MHigh-Throughput Craniofacial tissue engineeringR01DE016516 · NIDCR · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI LANGER, ROBERT SAMUEL · 2005 to 2014
$3.8MFunctions of the Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular EndotheliumK08HL096834 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI CHAN, STEPHEN Y · 2010 to 2014
$687kSchistosomiasis Associated Pulmonary Arterial HypertensionK08HL105536 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI GRAHAM, BRIAN BARKLEY · 2011 to 2015
$653kIntramural NIH HHSNCI NIH HHS U54 CA151884NCI NIH HHS U54-CA151884NHLBI NIH HHS K08 HL096834NHLBI NIH HHS K08HL096834NHLBI NIH HHS K08 HL105536NHLBI NIH HHS R01 HL122596NIBIB NIH HHS EB000244NIBIB NIH HHS R01 EB000244NIBIB NIH HHS R37 EB000244NIDCR NIH HHS R01 DE016516NIDCR NIH HHS R01-DE016516-06Wellcome TrustWellcome Trust 098051
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.
Indexed as
Genetic Predisposition to DiseaseIron DeficienciesAnimalsCells, CulturedEndothelial CellsFemaleHumansHypertension, PulmonaryHypoxiaIron-Sulfur ProteinsMiceMicroRNAsSulfurIron-Sulfur ProteinsISCU protein, humanMicroRNAsMIRN210 microRNA, humanSulfurendothelialiron–sulfurmetabolismmicroRNAmitochondria
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