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Abstract
013 Modulating mitochondrial dynamics as a novel cardioprotective strategy
  1. S B Ong,
  2. S Arjun,
  3. S Y Lim,
  4. S M Davidson,
  5. D M Yellon,
  6. D J Hausenloy
  1. Hatter Cardiovascular Institute, University College London, London, UK

Abstract

Introduction Mitochondria change their shape by undergoing either fusion or fission producing elongated interconnected or fragmented discrete networks, respectively. Whether alterations in mitochondrial morphology impact on the heart's susceptibility to ischaemia-reperfusion injury is unknown. We hypothesised that inducing mitochondrial fusion protects the heart against ischaemia-reperfusion injury.

Methods and Results In response to ischaemia, mitochondria in HL-1 cells (a cardiac-derived cell line) were shown to undergo fragmentation, a process which could be prevented by a dominant negative construct of Dynamin-related protein 1 (Drp1, a known mitochondrial fission protein). Inducing mitochondrial fusion in HL-1 cells by over-expressing either mitofusin 1 or 2 (known mitochondrial fusion proteins) or Drp1K38A (a dominant negative mutant form of Drp1): increased the proportion of cells containing elongated mitochondria (65±4%, 69±5%, 63±6%, respectively, vs 46±6% in control:N=80 cells/group; p<0.05); decreased mitochondrial permeability transition pore sensitivity (by 2.4±0.5, 2.3±0.7, 2.4±0.3-fold, respectively; N=80 cells/group: p<0.05); and reduced cell death following simulated ischaemia-reperfusion injury (11.6±3.9%, 16.2±3.9%, 12.1±2.9%, respectively, vs 41.8±4.1% in control:N=320 cells/group:p<0.05). Pharmacologically inducing mitochondrial fusion using mdivi-1, a small molecule Drp1 inhibitor, reproduced the beneficial effects. Crucially, elongated interfibrillar mitochondria were identified in the adult rodent heart using confocal and electron microscopy. Finally, inducing mitochondrial fusion with mdivi-1 in adult murine cardiomyocytes reduced cell death following simulated ischaemia-reperfusion injury (34.0±1.9% vs 46.0±1.1%:N>250 cells/group:p<0.05), and reduced infarct size in the in vivo murine heart (21.0±2.2% vs 48.0±4.5% in control;N=6 animals/group:p<0.05).

Conclusions Inducing mitochondrial fusion protects the heart against ischaemia-reperfusion injury. These findings provide a novel pharmacological target for cardioprotection.

  • mitochondria
  • mitochondrial permeability transition pore
  • ischaemia-reperfusion injury

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