The novel role of mitochondrial morphology in
Doctoral thesis, UCL (University College London).
Background– Mitochondria are able to change their morphology by undergoing either ‘fusion’ to form elongated interconnected networks or ‘fission’ to generate fragmented disconnected mitochondria. We investigated whether changes in mitochondrial morphology influence susceptibility of the heart to ischaemiareperfusion injury (IRI). We hypothesised that promoting mitochondrial fusion protects the heart against IRI by inhibiting mitochondrial permeability transition pore (mPTP) opening. Methods/Results– Mitochondrial fusion was induced in a HL-1 cardiac cell line by: 1), over-expressing Mitofusin 1 or 2 (known mitochondrial fusion proteins) or Drp1K38A (a dominant negative mutant form of Drp1, a known mitochondrial fission protein), 2), using the drug mdivi-1 (a Drp1 small molecule inhibitor) and 3), over-expressing or pharmacologically activating Akt1 (a known pro-survival kinase involved in growth and proliferation). Promoting mitochondrial fusion decreased mitochondrial permeability transition pore (mPTP) sensitivity and reduced cell death following simulated IRI (SIRI). In contrast, inducing mitochondrial fragmentation by over-expressing hFis1 (a known mitochondrial fission protein), enhanced cell death following SIRI but had no effect on mPTP opening. Treatment with mdivi-1 decreased mPTP sensitivity and reduced cell death in both HL-1 cells and adult murine cardiomyocytes following SIRI, and reduced myocardial infarct size in the adult murine heart. Elongated adult cardiac mitochondria (4-6 μM) were observed using electron and confocal microscopy in adult murine hearts and these were increased with mdivi-1 treatment prior to ischaemia. Conclusions– For the first time we show that modulating mitochondrial morphology can influence the susceptibility of the heart to IRI. We show that inducing mitochondrial fusion protects the heart against IRI. These findings provide a novel pharmacological target for cardioprotection.
|Title:||The novel role of mitochondrial morphology in cardioprotection|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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