Skip to main content
SpringerLink
Log in

Dynamin-related protein 1 as a therapeutic target in cardiac arrest

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

Abstract

Despite improvements in cardiopulmonary resuscitation (CPR) quality, defibrillation technologies, and implementation of therapeutic hypothermia, less than 10 % of out-of-hospital cardiac arrest (OHCA) victims survive to hospital discharge. New resuscitation therapies have been slow to develop, in part, because the pathophysiologic mechanisms critical for resuscitation are not understood. During cardiac arrest, systemic cessation of blood flow results in whole body ischemia. CPR and the restoration of spontaneous circulation (ROSC), both result in immediate reperfusion injury of the heart that is characterized by severe contractile dysfunction. Unlike diseases of localized ischemia/reperfusion (IR) injury (myocardial infarction and stroke), global IR injury of organs results in profound organ dysfunction with far shorter ischemic times. The two most commonly injured organs following cardiac arrest resuscitation, the heart and brain, are critically dependent on mitochondrial function. New insights into mitochondrial dynamics and the role of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) in apoptosis have made targeting these mechanisms attractive for IR therapy. In animal models, inhibiting Drp1 following IR injury or cardiac arrest confers protection to both the heart and brain. In this review, the relationship of the major mitochondrial fission protein Drp1 to ischemic changes in the heart and its targeting as a new therapeutic target following cardiac arrest are discussed.

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

Similar content being viewed by others

References

  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S et al (2014) Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 129:e28–e292

    Article  PubMed  Google Scholar 

  2. Laver S, Farrow C, Turner D, Nolan J (2004) Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 30:2126–2128

    Article  PubMed  Google Scholar 

  3. Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC et al (2008) Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 118:2452–2483

    Article  PubMed  Google Scholar 

  4. Paradis NA, Martin GB, Rivers EP, Goetting MG, Appleton TJ, Feingold M, Nowak RM (1990) Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 263:1106–1113

    Article  CAS  PubMed  Google Scholar 

  5. Nolan JP, Neumar RW, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC et al (2008) Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 79:350–379

    Article  PubMed  Google Scholar 

  6. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL (2001) Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure. J Mol Cell Cardiol 33:1065–1089

    Article  CAS  PubMed  Google Scholar 

  7. Gazmuri RJ, Radhakrishnan J (2012) Protecting mitochondrial bioenergetic function during resuscitation from cardiac arrest. Crit Care Clin 28:245–270

    Article  PubMed Central  PubMed  Google Scholar 

  8. Archer SL (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 369:2236–2251

    Article  CAS  PubMed  Google Scholar 

  9. Kane LA, Youle RJ (2010) Mitochondrial fission and fusion and their roles in the heart. J Mol Med (Berl) 88:971–979

    Article  Google Scholar 

  10. Kasahara A, Scorrano L (2014) Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol 24:761–770

    Article  CAS  PubMed  Google Scholar 

  11. Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022

    Article  CAS  PubMed  Google Scholar 

  12. Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, Banathy A, Morrow E, Ryan JJ, Archer SL (2014) Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. FASEB J 28:316–326

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Imoto M, Tachibana I, Urrutia R (1998) Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p. J Cell Sci 111(Pt 10):1341–1349

    CAS  PubMed  Google Scholar 

  14. Shin HW, Shinotsuka C, Torii S, Murakami K, Nakayama K (1997) Identification and subcellular localization of a novel mammalian dynamin-related protein homologous to yeast Vps1p and Dnm1p. J Biochem 122:525–530

    Article  CAS  PubMed  Google Scholar 

  15. Yoon Y, Pitts KR, Dahan S, McNiven MA (1998) A novel dynamin-like protein associates with cytoplasmic vesicles and tubules of the endoplasmic reticulum in mammalian cells. J Cell Biol 140:779–793

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Kamimoto T, Nagai Y, Onogi H, Muro Y, Wakabayashi T, Hagiwara M (1998) Dymple, a novel dynamin-like high molecular weight GTPase lacking a proline-rich carboxyl-terminal domain in mammalian cells. J Biol Chem 273:1044–1051

    Article  CAS  PubMed  Google Scholar 

  17. Bleazard W, McCaffery JM, King EJ, Bale S, Mozdy A, Tieu Q, Nunnari J, Shaw JM (1999) The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol 1:298–304

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (1998) A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 143:351–358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem 288:27584–27593

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Koirala S, Guo Q, Kalia R, Bui HT, Eckert DM, Frost A, Shaw JM (2013) Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission. Proc Natl Acad Sci U S A 110:E1342–E1351

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12:2245–2256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. van der Bliek AM (2000) A mitochondrial division apparatus takes shape. J Cell Biol 151:F1–F4

    Article  PubMed Central  PubMed  Google Scholar 

  28. Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basanez G, Meda P et al (2010) Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142:889–901

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Macdonald PJ, Stepanyants N, Mehrotra N, Mears JA, Qi X, Sesaki H, Ramachandran R (2014) A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission. Mol Biol Cell 25:1905–1915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Chang CR, Manlandro CM, Arnoult D, Stadler J, Posey AE, Hill RB, Blackstone C (2010) A lethal de novo mutation in the middle domain of the dynamin-related GTPase Drp1 impairs higher order assembly and mitochondrial division. J Biol Chem 285:32494–32503

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV (2007) A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 356:1736–1741

    Article  CAS  PubMed  Google Scholar 

  32. Strack S, Cribbs JT (2012) Allosteric modulation of Drp1 mechanoenzyme assembly and mitochondrial fission by the variable domain. J Biol Chem 287:10990–11001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. 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 

  34. Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P (2011) Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev 67:103–118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Strack S, Wilson TJ, Cribbs JT (2013) Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules. J Cell Biol 201:1037–1051

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Uo T, Dworzak J, Kinoshita C, Inman DM, Kinoshita Y, Horner PJ, Morrison RS (2009) Drp1 levels constitutively regulate mitochondrial dynamics and cell survival in cortical neurons. Exp Neurol 218:274–285

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A 105:15803–15808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8:939–944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282:21583–21587

    Article  CAS  PubMed  Google Scholar 

  40. Wang W, Wang Y, Long J, Wang J, Haudek SB, Overbeek P, Chang BH, Schumacker PT, Danesh FR (2012) Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 15:186–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. 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 

  42. 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 

  43. 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 

  44. Yu T, Jhun BS, Yoon Y (2011) High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Antioxid Redox Signal 14:425–437

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Chou CH, Lin CC, Yang MC, Wei CC, Liao HD, Lin RC, Tu WY, Kao TC, Hsu CM, Cheng JT et al (2012) GSK3beta-mediated Drp1 phosphorylation induced elongated mitochondrial morphology against oxidative stress. PLoS One 7:e49112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Dezfulian C, Shiva S, Alekseyenko A, Pendyal A, Beiser DG, Munasinghe JP, Anderson SA, Chesley CF, Vanden Hoek TL, Gladwin MT (2009) Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I. Circulation 120:897–905

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Sun J, Murphy E (2010) Protein S-nitrosylation and cardioprotection. Circ Res 106:285–296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Bossy B, Petrilli A, Klinglmayr E, Chen J, Lutz-Meindl U, Knott AB, Masliah E, Schwarzenbacher R, Bossy-Wetzel E (2010) S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer's disease. J Alzheimers Dis 20(Suppl 2):S513–S526

    PubMed Central  PubMed  Google Scholar 

  50. Harder Z, Zunino R, McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14:340–345

    Article  CAS  PubMed  Google Scholar 

  51. Wasiak S, Zunino R, McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 177:439–450

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Zunino R, Braschi E, Xu L, McBride HM (2009) Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem 284:17783–17795

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Braschi E, Zunino R, McBride HM (2009) MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 10:748–754

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, Chang CR, Arnoult D, Keller PJ, Hong Y, Blackstone C, Feldman EL (2009) SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J 23:3917–3927

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Gawlowski T, Suarez J, Scott B, Torres-Gonzalez M, Wang H, Schwappacher R, Han X, Yates JR 3rd, Hoshijima M, Dillmann W (2012) Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-beta-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem 287:30024–30034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S (2006) MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 7:1019–1022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Wang H, Song P, Du L, Tian W, Yue W, Liu M, Li D, Wang B, Zhu Y, Cao C et al (2011) Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem 286:11649–11658

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, Masuda K, Otera H, Nakanishi Y, Nonaka I, Goto Y et al (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11:958–966

    Article  CAS  PubMed  Google Scholar 

  59. Wakabayashi J, Zhang Z, Wakabayashi N, Tamura Y, Fukaya M, Kensler TW, Iijima M, Sesaki H (2009) The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol 186:805–816

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S, Toli J, Nomura M, Mihara K, Egashira K, Ohishi M et al (2015) Endogenous drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res 116:264–278

    Article  CAS  PubMed  Google Scholar 

  61. Kageyama Y, Hoshijima M, Seo K, Bedja D, Sysa-Shah P, Andrabi SA, Chen W, Hoke A, Dawson VL, Dawson TM et al (2014) Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J 33:2798–2813

    Article  CAS  PubMed  Google Scholar 

  62. Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M (2003) Dynamin-like protein 1 is involved in peroxisomal fission. J Biol Chem 278:8597–8605

    Article  CAS  PubMed  Google Scholar 

  63. Zepeda R, Kuzmicic J, Parra V, Troncoso R, Pennanen C, Riquelme JA, Pedrozo Z, Chiong M, Sanchez G, Lavandero S (2014) Drp1 loss-of-function reduces cardiomyocyte oxygen dependence protecting the heart from ischemia-reperfusion injury. J Cardiovasc Pharmacol 63:477–487

    Article  CAS  PubMed  Google Scholar 

  64. Pennanen C, Parra V, Lopez-Crisosto C, Morales PE, Del Campo A, Gutierrez T, Rivera-Mejias P, Kuzmicic J, Chiong M, Zorzano A et al (2014) Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2 + −calcineurin signaling pathway. J Cell Sci 127:2659–2671

    Article  CAS  PubMed  Google Scholar 

  65. Din S, Mason M, Volkers M, Johnson B, Cottage CT, Wang Z, Joyo AY, Quijada P, Erhardt P, Magnuson NS et al (2013) Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation. Proc Natl Acad Sci U S A 110:5969–5974

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Park SW, Kim KY, Lindsey JD, Dai Y, Heo H, Nguyen DH, Ellisman MH, Weinreb RN, Ju WK (2011) A selective inhibitor of drp1, mdivi-1, increases retinal ganglion cell survival in acute ischemic mouse retina. Invest Ophthalmol Vis Sci 52:2837–2843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. 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 

  68. Disatnik MH, Ferreira JC, Campos JC, Gomes KS, Dourado PM, Qi X, Mochly-Rosen D (2013) Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction. J Am Heart Assoc 2:e000461

    Article  PubMed Central  PubMed  Google Scholar 

  69. Yeh ST, Lee HL, Aune SE, Chen CL, Chen YR, Angelos MG (2009) Preservation of mitochondrial function with cardiopulmonary resuscitation in prolonged cardiac arrest in rats. J Mol Cell Cardiol 47:789–797

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Brooks C, Wei Q, Cho SG, Dong Z (2009) Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest 119:1275–1285

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Wang JX, Jiao JQ, Li Q, Long B, Wang K, Liu JP, Li YR, Li PF (2011) miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med 17:71–78

    Article  PubMed  Google Scholar 

  72. Kern KB, Hilwig RW, Rhee KH, Berg RA (1996) Myocardial dysfunction after resuscitation from cardiac arrest: an example of global myocardial stunning. J Am Coll Cardiol 28:232–240

    Article  CAS  PubMed  Google Scholar 

  73. Kern KB (2002) Postresuscitation myocardial dysfunction. Cardiol Clin 20:89–101

    Article  PubMed  Google Scholar 

  74. Sharp WW, Beiser DG, Fang YH, Han M, Piao L, Varughese J, Archer SL (2015) Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model. Crit Care Med 43:e38–e47

    Article  CAS  PubMed  Google Scholar 

  75. Edoute Y, van der Merwe E, Sanan D, Kotze JC, Steinmann C, Lochner A (1983) Normothermic ischemic cardiac arrest of the isolated working rat heart. Effects of time and reperfusion on myocardial ultrastructure, mitochondrial oxidative function, and mechanical recovery. Circ Res 53:663–678

    Article  CAS  PubMed  Google Scholar 

  76. Perez-Pinzon MA, Stetler RA, Fiskum G (2012) Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab 32:1362–1376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Zuo W, Zhang S, Xia CY, Guo XF, He WB, Chen NH (2014) Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: the role of inhibition of Drp1 in ischemic brain damage. Neuropharmacology 86:103–115

    Article  CAS  PubMed  Google Scholar 

  78. Wang J, Wang P, Li S, Wang S, Li Y, Liang N, Wang M (2014) Mdivi-1 prevents apoptosis induced by ischemia-reperfusion injury in primary hippocampal cells via inhibition of reactive oxygen species-activated mitochondrial pathway. J Stroke Cerebrovasc Dis 23:1491–1499

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Institutes of Health HL103901-01A1 and R03 HL110826-01A1. The Department of Medicine, University of Chicago, provided additional funding for Dr. Sharp’s work.

Conflict of interest

Dr. Sharp has no significant conflicts of interest to report.

Author information

Authors and Affiliations

  1. Section of Emergency Medicine, Department of Medicine, University of Chicago, 5841 S. Maryland Ave, MC 5068, Chicago, IL, 60637, USA

    Willard W. Sharp

Authors
  1. Willard W. Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Willard W. Sharp.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharp, W.W. Dynamin-related protein 1 as a therapeutic target in cardiac arrest. J Mol Med 93, 243–252 (2015). https://doi.org/10.1007/s00109-015-1257-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-015-1257-3

Keywords

Search

Navigation