title: Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.
abstract: BACKGROUND
  Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury.
  
  
  RESULTS
  In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1(K38A), a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65+/-4%, 69+/-5%, and 63+/-6%, respectively, versus 46+/-6% in control: n=80 cells per group; P<0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4+/-0.5-, 2.3+/-0.7-, and 2.4+/-0.3-fold, respectively; n=80 cells per group; P<0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6+/-3.9%, 16.2+/-3.9%, and 12.1+/-2.9%, respectively, versus 41.8+/-4.1% in control: n=320 cells per group; P<0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6+/-0.5% to 14.5+/-2.8% (P=0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0+/-2.2% with mitochondrial division inhibitor-1 versus 48.0+/-4.5% in control; n=6 animals per group; P<0.05).
  
  
  CONCLUSIONS
  Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.
authors.affiliation: The Hatter Cardiovascular Institute, University College London Hospital, UK.
authors.forename: Sang-Bing
authors.initials: SB
authors.lastname: Ong
authors.forename: Sapna
authors.initials: S
authors.lastname: Subrayan
authors.forename: Shiang Y
authors.initials: SY
authors.lastname: Lim
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
mesh_terms: D000367:Age Factors; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D008561:Membrane Fusion / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D052999:Quinazolinones / Q000494:pharmacology*; D014162:Transfection
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D002316:Cardiotonic Agents; D008869:Microtubule-Associated Proteins; D052999:Quinazolinones; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins