Skip to main content
SpringerLink
Log in

Mitochondrial dynamics in pulmonary arterial hypertension

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Pulmonary arterial hypertension (PAH) is an idiopathic cardiopulmonary disease characterized by obstruction of small pulmonary arteries. Vascular obstruction is the consequence of excessive proliferation and apoptosis resistance of vascular cells, as well as inflammation, thrombosis, and vasoconstriction. Vascular obstruction increases the afterload faced by the right ventricle (RV), leading to RV failure. The proliferative, obstructive vasculopathy of PAH shares several mitochondrial abnormalities with cancer, notably a shift to aerobic glycolysis and mitochondrial fragmentation. Mitochondria in the pulmonary artery smooth muscle cell (PASMC) normally serve as oxygen sensors. In PAH, acquired mitochondrial abnormalities, including epigenetic silencing of superoxide dismutase (SOD2), disrupt oxygen sensing creating a pseudo-hypoxic environment characterized by normoxic activation of hypoxia-inducible factor-1α (HIF-1α). The resulting metabolic shift to aerobic glycolysis (the Warburg phenomenon) reflects inhibition of pyruvate dehydrogenase by pyruvate dehydrogenase kinases. In addition, altered mitochondrial dynamics result in mitochondrial fragmentation. The molecular basis of this structural change includes upregulation and activation of fission mediators, notably dynamin-related protein 1 (DRP-1), and downregulation of fusion mediators, especially mitofusin-2 (MFN2). These pathogenic mitochondrial abnormalities offer new therapeutic targets. Inhibition of mitotic fission or enhancement of fusion in PAH PASMC slows cell proliferation, causes cell cycle arrest, and induces apoptosis. DRP-1 inhibition or MFN2 gene therapy can regress PAH in experimental models of PAH. This review focuses on the etiology of mitochondrial fragmentation in PAH and explores the therapeutic implications of mitochondrial dynamics in the pulmonary vasculature and RV.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL (2005) Acute oxygen-sensing mechanisms. N Engl J Med 353:2042–2055

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065

    Article  CAS  PubMed  Google Scholar 

  4. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A 106:11960–11965

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, Salgia R, Husain AN, Wietholt C, Archer SL (2012) Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 26:2175–2186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Cribbs JT, Strack S (2009) Functional characterization of phosphorylation sites in dynamin-related protein 1. Methods Enzymol 457:231–253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M (2008) CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182:573–585

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, Thenappan T, Piao L, Zhang HJ, Pogoriler J et al (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110:1484–1497

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS et al (2006) An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113:2630–2641

    Article  CAS  PubMed  Google Scholar 

  10. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN et al (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121:2661–2671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Archer SL, Fang YH, Ryan JJ, Piao L (2013) Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm Circ 3:144–152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS et al (2009) ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 119:2250–2294

    Article  PubMed  Google Scholar 

  13. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F et al (2013) Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 62:D42–D50

    Article  PubMed  Google Scholar 

  14. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34–D41

    Article  PubMed  Google Scholar 

  15. Ryan JJ, Archer SL (2014) The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res 115:176–188

    Article  CAS  PubMed  Google Scholar 

  16. Hatton N, Ryan JJ (2014) Sex differences in response to pulmonary arterial hypertension therapy: is what’s good for the goose, good for the gander? Chest 145:1184–1186

    Article  PubMed  Google Scholar 

  17. Ling Y, Johnson MK, Kiely DG, Condliffe R, Elliot CA, Gibbs JS, Howard LS, Pepke-Zaba J, Sheares KK, Corris PA et al (2012) Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 186:790–796

    Article  PubMed  Google Scholar 

  18. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F et al (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173:1023–1030

    Article  PubMed  Google Scholar 

  19. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Herve P, Simonneau G (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111:3105–3111

    Article  CAS  PubMed  Google Scholar 

  20. Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF (2009) Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 120:1951–1960

    Article  PubMed  Google Scholar 

  21. Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl) 88:47–60

    Article  CAS  Google Scholar 

  22. Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED (2013) A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med (Berl) 91:1315–1327

    Article  CAS  Google Scholar 

  23. Thenappan T, Ryan JJ, Archer SL (2012) Evolving epidemiology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186:707–709

    Article  PubMed Central  PubMed  Google Scholar 

  24. Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M (2010) Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 35:1079–1087

    Article  CAS  PubMed  Google Scholar 

  25. Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, Poubeau P, Cerrina J, Duroux P, Drouet L (1995) Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249–254

    Article  CAS  PubMed  Google Scholar 

  26. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327:70–75

    Article  CAS  PubMed  Google Scholar 

  27. Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC, Bevan JA, Fishman MC, Zapol WM (1997) Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res 81:34–41

    Article  CAS  PubMed  Google Scholar 

  28. Stewart DJ, Levy RD, Cernacek P, Langleben D (1991) Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 114:464–469

    Article  CAS  PubMed  Google Scholar 

  29. Reeve HL, Michelakis E, Nelson DP, Weir EK, Archer SL (2001) Alterations in a redox oxygen sensing mechanism in chronic hypoxia. J Appl Physiol (1985) 90:2249–2256

    CAS  Google Scholar 

  30. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ (1998) Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98:1400–1406

    Article  CAS  PubMed  Google Scholar 

  31. Ryan JJ, Marsboom G, Fang YH, Toth PT, Morrow E, Luo N, Piao L, Hong Z, Ericson K, Zhang HJ et al (2013) PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med 187:865–878

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED (2005) Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 115:1479–1491

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840

    Article  CAS  PubMed  Google Scholar 

  34. Cowan KN, Jones PL, Rabinovitch M (2000) Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 105:21–34

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Huertas A, Perros F, Tu L, Cohen-Kaminsky S, Montani D, Dorfmuller P, Guignabert C, Humbert M (2014) Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation 129:1332–1340

    Article  PubMed  Google Scholar 

  36. Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J et al (2005) Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol 45:1849–1855

    Article  CAS  PubMed  Google Scholar 

  37. Hagan G, Southwood M, Treacy C, Ross RM, Soon E, Coulson J, Sheares K, Screaton N, Pepke-Zaba J, Morrell NW et al (2011) (18)FDG PET imaging can quantify increased cellular metabolism in pulmonary arterial hypertension: a proof-of-principle study. Pulm Circ 1:448–455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J et al (2012) Lung (1)(8)F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185:670–679

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. McMurtry IF, Morris KG, Petrun MD (1980) Blunted hypoxic vasoconstriction in lungs from short-term high-altitude rats. Am J Physiol 238:H849–H857

    CAS  PubMed  Google Scholar 

  40. Reeve HL, Michelakis E, Nelson DP, Weir EK, Archer SL (2001) Alterations in a redox oxygen sensing mechanism in chronic hypoxia. J Appl Physiol (1985) 90:2249–2256

    CAS  Google Scholar 

  41. Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G et al (2003) In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107:2037–2044

    Article  CAS  PubMed  Google Scholar 

  42. Shimoda LA, Manalo DJ, Sham JS, Semenza GL, Sylvester JT (2001) Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 281:L202–L208

    CAS  PubMed  Google Scholar 

  43. Archer SL, Weir EK, Wilkins MR (2010) Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 121:2045–2066

    Article  PubMed Central  PubMed  Google Scholar 

  44. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL (2002) Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105:244–250

    Article  CAS  PubMed  Google Scholar 

  45. Fang YH, Piao L, Hong Z, Toth PT, Marsboom G, Bache-Wiig P, Rehman J, Archer SL (2012) Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle. J Mol Med (Berl) 90:31–43

    Article  CAS  Google Scholar 

  46. Sutendra G, Michelakis ED (2013) Pulmonary arterial hypertension: challenges in translational research and a vision for change. Sci Transl Med 5:208sr205

    Article  Google Scholar 

  47. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740–L754

    CAS  PubMed  Google Scholar 

  49. Fessel JP, Hamid R, Wittmann BM, Robinson LJ, Blackwell T, Tada Y, Tanabe N, Tatsumi K, Hemnes AR, West JD (2012) Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming. Pulm Circ 2:201–213

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Archer SL, Huang J, Henry T, Peterson D, Weir EK (1993) A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 73:1100–1112

    Article  CAS  PubMed  Google Scholar 

  51. Weir EK, Archer SL (1995) The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 9:183–189

    CAS  PubMed  Google Scholar 

  52. Sylvester JT, Shimoda LA, Aaronson PI, Ward JP (2012) Hypoxic pulmonary vasoconstriction. Physiol Rev 92:367–520

    Article  CAS  PubMed  Google Scholar 

  53. Archer SL, Will JA, Weir EK (1986) Redox status in the control of pulmonary vascular tone. Herz 11:127–141

    CAS  PubMed  Google Scholar 

  54. Archer SL, Nelson DP, Weir EK (1989) Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung. J Appl Physiol (1985) 67:1903–1911

    CAS  Google Scholar 

  55. Waypa GB, Marks JD, Mack MM, Boriboun C, Mungai PT, Schumacker PT (2002) Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ Res 91:719–726

    Article  CAS  PubMed  Google Scholar 

  56. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK (2008) Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 294:H570–H578

    Article  CAS  PubMed  Google Scholar 

  57. Post JM, Hume JR, Archer SL, Weir EK (1992) Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 262:C882–C890

    CAS  PubMed  Google Scholar 

  58. Michelakis ED, Hampl V, Nsair A, Wu X, Harry G, Haromy A, Gurtu R, Archer SL (2002) Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res 90:1307–1315

    Article  CAS  PubMed  Google Scholar 

  59. Hong Z, Kutty S, Toth PT, Marsboom G, Hammel JM, Chamberlain C, Ryan JJ, Zhang HJ, Sharp WW, Morrow E et al (2013) Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus. Circ Res 112:802–815

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Maggiorini M (2010) Prevention and treatment of high-altitude pulmonary edema. Prog Cardiovasc Dis 52:500–506

    Article  CAS  PubMed  Google Scholar 

  61. Wolin MS (2012) Novel role for the regulation of mitochondrial fission by hypoxia inducible factor-1alpha in the control of smooth muscle remodeling and progression of pulmonary hypertension. Circ Res 110:1395–1397

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Hickey MM, Richardson T, Wang T, Mosqueira M, Arguiri E, Yu H, Yu QC, Solomides CC, Morrisey EE, Khurana TS et al (2010) The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest 120:827–839

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D et al (2002) Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32:614–621

    Article  CAS  PubMed  Google Scholar 

  64. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet SN, Haromy A, Harry G, Moudgil R, McMurtry MS et al (2006) An abnormal mitochondrial-HIF-1-Kv channel pathway disrupts oxygen-sensing and triggers pulmonary arterial hypertension (PAH) in fawn-hooded rats: similarities to human PAH. Circulation 113:2630–2641

    Article  CAS  PubMed  Google Scholar 

  65. Piao L, Sidhu VK, Fang YH, Ryan JJ, Parikh KS, Hong Z, Toth PT, Morrow E, Kutty S, Lopaschuk GD et al (2013) FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med (Berl) 91:333–346

    Article  CAS  Google Scholar 

  66. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  67. Ryan JJ, Marsboom G, Fang YH, Toth PT, Morrow E, Luo N, Piao L, Hong Z, Ericson K, Zhang HJ et al (2013) PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med. doi:10.1164/rccm.201209-1687OC

    PubMed Central  PubMed  Google Scholar 

  68. Zhu PP, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C (2004) Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem 279:35967–35974

    Article  CAS  PubMed  Google Scholar 

  69. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282:11521–11529

    Article  CAS  PubMed  Google Scholar 

  70. Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M (2004) Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 428:190–193

    Article  CAS  PubMed  Google Scholar 

  71. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Qi X, Qvit N, Su YC, Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 126:789–802

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H (2005) Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 280:25060–25070

    Article  CAS  PubMed  Google Scholar 

  74. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  PubMed  Google Scholar 

  75. Santel A, Frank S, Gaume B, Herrler M, Youle RJ, Fuller MT (2003) Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci 116:2763–2774

    Article  CAS  PubMed  Google Scholar 

  76. Chen KH, Guo X, Ma D, Guo Y, Li Q, Yang D, Li P, Qiu X, Wen S, Xiao RP et al (2004) Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol 6:872–883

    Article  CAS  PubMed  Google Scholar 

  77. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811–2821

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Soriano FX, Liesa M, Bach D, Chan DC, Palacin M, Zorzano A (2006) Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 55:1783–1791

    Article  CAS  PubMed  Google Scholar 

  79. Chen KH, Dasgupta A, Ding J, Indig FE, Ghosh P, Longo DL (2014) Role of mitofusin 2 (Mfn2) in controlling cellular proliferation. FASEB J 28:382–394

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140–1151

    Article  PubMed  Google Scholar 

  81. Piao L, Fang YH, Parikh K, Ryan JJ, Toth PT, Archer SL (2013) Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension. J Mol Med (Berl) 91:1185–1197

    Article  CAS  Google Scholar 

  82. Rich S, Pogoriler J, Husain AN, Toth PT, Gomberg-Maitland M, Archer SL (2010) Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest 138:1234–1239

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Chen Y, Liu Y, Dorn GW 2nd (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109:1327–1331

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Ngoh GA, Papanicolaou KN, Walsh K (2012) Loss of mitofusin 2 promotes endoplasmic reticulum stress. J Biol Chem 287:20321–20332

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Papanicolaou KN, Kikuchi R, Ngoh GA, Coughlan KA, Dominguez I, Stanley WC, Walsh K (2012) Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res 111:1012–1026

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S, Toli J, Nomura M, Mihara K, Egashira K, Ohishi M et al (2014) Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. doi:10.1161/CIRCRESAHA.116.303356

    Google Scholar 

  88. Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I, O’Shea KM, Riley DD, Lugus JJ, Colucci WS, Lederer WJ et al (2011) Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 31:1309–1328

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, Drake JI, Farkas L, Kraskauskas D, Wijesinghe DS et al (2013) Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail 6:136–144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by NIH-RO1-HL071115, 1RC1HL099462-01 (S.A.) and the American Heart Association (AHA), CIHR Vascular Network (A.D.).

Disclosure

Patent for use of PDK inhibitors in cancer (not commercialized).

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

    John Ryan & Jessica Huston

  2. Department of Medicine, Queen’s University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada

    Asish Dasgupta, Kuang-Huieh Chen & Stephen L. Archer

Authors
  1. John Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asish Dasgupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessica Huston
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kuang-Huieh Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen L. Archer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen L. Archer.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ryan, J., Dasgupta, A., Huston, J. et al. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med 93, 229–242 (2015). https://doi.org/10.1007/s00109-015-1263-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-015-1263-5

Keywords

Search

Navigation