title: 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 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.
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Annis
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Hale
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.affiliation: 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.
authors.forename: James E
authors.initials: JE
authors.lastname: Dahlman
authors.affiliation: 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.
authors.forename: Craig
authors.initials: C
authors.lastname: Hemann
authors.affiliation: 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.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Opotowsky
authors.affiliation: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sara O
authors.initials: SO
authors.lastname: Vargas
authors.affiliation: Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rosas
authors.affiliation: 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.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.affiliation: Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.affiliation: Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.affiliation: Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
authors.affiliation: Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.affiliation: Department of Cardiothoracic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Saggar
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: W Dean
authors.initials: WD
authors.lastname: Wallace
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.affiliation: 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.
authors.forename: Omar F
authors.initials: OF
authors.lastname: Khan
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bader
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.affiliation: Celsion-EGEN, Inc., Huntsville, AL, USA.
authors.forename: Majed
authors.initials: M
authors.lastname: Matar
authors.affiliation: Celsion-EGEN, Inc., Huntsville, AL, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Polach
authors.affiliation: Department of Cardiology, University of Bergen, Bergen, Norway.
authors.forename: Nicolai M
authors.initials: NM
authors.lastname: Johannessen
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Haydn M
authors.initials: HM
authors.lastname: Prosser
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: 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.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.affiliation: Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Systrom
authors.affiliation: Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Jin
authors.affiliation: Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA sychan@partners.org.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D000090463:Iron Deficiencies; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D013455:Sulfur / Q000172:deficiency*
chemical_list: C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D013455:Sulfur
keywords: endothelial; iron–sulfur; metabolism; microRNA; mitochondria
references.citation: Adv Pulm Hypertens. 2010 Apr 1;9(2):92-100
references.pmid: 34422153
references.citation: J Clin Invest. 1991 Oct;88(4):1197-206
references.pmid: 1918374
references.citation: Eur Respir J. 2012 Feb;39(2):319-28
references.pmid: 21885394
references.citation: Circulation. 2012 Mar 27;125(12):1520-32
references.pmid: 22371328
references.citation: J Inherit Metab Dis. 2005;28(6):1081-9
references.pmid: 16435201
references.citation: J Immunol. 2013 Sep 15;191(6):3037-3048
references.pmid: 23960236
references.citation: Nat Chem Biol. 2011 Nov 27;8(1):125-32
references.pmid: 22119860
references.citation: Oncogene. 2006 Aug 7;25(34):4647-62
references.pmid: 16892079
references.citation: Med Sci Sports Exerc. 2008 Jan;40(1):3-8
references.pmid: 18091026
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1342-7
references.pmid: 17227868
references.citation: Mol Genet Metab. 2014 Mar;111(3):353-359
references.pmid: 24485043
references.citation: Chem Biol. 2009 Dec 24;16(12):1299-308
references.pmid: 20064440
references.citation: Am J Respir Crit Care Med. 2012 Feb 1;185(3):260-6
references.pmid: 22077069
references.citation: Am J Hum Genet. 2008 Mar;82(3):652-60
references.pmid: 18304497
references.citation: J Inherit Metab Dis. 2008 Dec;31 Suppl 3:497-503
references.pmid: 18181029
references.citation: Cell Metab. 2013 Feb 5;17(2):271-81
references.pmid: 23395173
references.citation: J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-41
references.pmid: 24355639
references.citation: Circulation. 2008 Nov 18;118(21):2183-9
references.pmid: 18981305
references.citation: J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D4-12
references.pmid: 24355640
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Oct;301(4):R873-84
references.pmid: 21813873
references.citation: Nat Biotechnol. 2011 Aug 07;29(9):840-5
references.pmid: 21822254
references.citation: Chest. 2001 Mar;119(3):824-32
references.pmid: 11243964
references.citation: Thorax. 2011 Apr;66(4):326-32
references.pmid: 21297151
references.citation: J Appl Physiol (1985). 1987 Aug;63(2):521-30
references.pmid: 3654410
references.citation: Cell Metab. 2009 Oct;10(4):273-84
references.pmid: 19808020
references.citation: Eur J Clin Invest. 2013 Aug;43(8):855-65
references.pmid: 23617881
references.citation: Eur Respir J. 2009 Oct;34(4):888-94
references.pmid: 19324955
references.citation: Brain Dev. 2012 Nov;34(10):866-8
references.pmid: 22455997
references.citation: Blood. 2011 Mar 31;117(13):3485-93
references.pmid: 21258008
references.citation: Circ Res. 2012 Feb 3;110(3):483-95
references.pmid: 22302755
references.citation: Am J Respir Cell Mol Biol. 2014 Jun;50(6):1084-95
references.pmid: 24392990
references.citation: Acta Med Scand. 1969 Mar;185(3):153-66
references.pmid: 5811159
references.citation: Circulation. 2006 Jun 6;113(22):2630-41
references.pmid: 16735674
references.citation: J Clin Invest. 2014 Aug;124(8):3514-28
references.pmid: 24960162
references.citation: Cell Cycle. 2010 Mar 15;9(6):1072-83
references.pmid: 20237418
references.citation: J Biol Chem. 2012 Oct 5;287(41):34110-9
references.pmid: 22896707
references.citation: Am J Pathol. 2010 Mar;176(3):1130-8
references.pmid: 20110409
references.citation: Am J Respir Crit Care Med. 2012 Mar 15;185(6):670-9
references.pmid: 22246173
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Oct 15;303(8):L682-91
references.pmid: 22886504
references.citation: Biochim Biophys Acta. 2010 Jun;1802(6):539-44
references.pmid: 20206689
references.citation: EMBO J. 2000 Nov 1;19(21):5692-700
references.pmid: 11060020
references.citation: Science. 2012 Jul 13;337(6091):195-9
references.pmid: 22678362
references.citation: Trends Genet. 2008 Aug;24(8):398-407
references.pmid: 18606475
references.citation: Nat Nanotechnol. 2014 Aug;9(8):648-655
references.pmid: 24813696
references.citation: Biochim Biophys Acta. 2014 Nov;1843(11):2528-42
references.pmid: 24983771
references.citation: Science. 1997 Aug 1;277(5326):653-9
references.pmid: 9235882
references.citation: J Am Heart Assoc. 2013 Apr 22;2(2):e000121
references.pmid: 23608607
references.citation: J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S55-S66
references.pmid: 19555859
references.citation: Circ Res. 2009 Jan 30;104(2):236-44, 28p following 244
references.pmid: 19074475
references.citation: Antioxid Redox Signal. 2013 May 10;18(14):1739-52
references.pmid: 23244702
references.citation: Eur Respir J. 2011 Jun;37(6):1386-91
references.pmid: 20884742
references.citation: Nat Rev Cardiol. 2011 Jun 21;8(8):443-55
references.pmid: 21691314
references.citation: Am J Respir Crit Care Med. 2013 Mar 15;187(6):576-83
references.pmid: 23348976
references.citation: N Engl J Med. 2011 May 12;364(19):1795-806
references.pmid: 21561345
references.citation: Chest. 2012 Nov;142(5):1158-1165
references.pmid: 22539647
references.citation: J Am Coll Cardiol. 2011 Jul 12;58(3):300-9
references.pmid: 21737024
references.citation: Circ Res. 2011 Aug 19;109(5):543-53
references.pmid: 21719760
references.citation: BMC Nephrol. 2013 Sep 13;14:195
references.pmid: 24034276
references.citation: Dis Model Mech. 2012 Mar;5(2):155-64
references.pmid: 22382365
references.citation: Am J Hum Genet. 2011 Nov 11;89(5):656-67
references.pmid: 22077971
references.citation: Mol Ther. 2012 Jan;20(1):91-100
references.pmid: 21988874
references.citation: Med Sci Sports Exerc. 2011 Jun;43(6):983-9
references.pmid: 21085040