Targeting Mitochondria to Treat Heart Disease

European Coordinator:
  • OVIZE Michel, INSERM, Université Claude Bernard, Lyon (France)
North American Coordinator:
  • MURPHY Elisabeth, NIH NHLBI, Bethesda (USA)
Members:
  • Paolo BERNARDI, University of Padova (Italy)
  • Michael COHEN, Oregon Health and Science University, Portland, OR (USA)
  • Michael FORTE, Oregon Health and Science University, Portland, OR (USA)
  • Jeffery MOLKENTIN, Children’s Hospital Medical Center, Cincinnati, OH (USA)
  • Fabio DILISA, University of Padova (Italy)

According to current understanding, mitochondria are key participants in the mechanism of myocyte death after acute myocardial infarction and during heart failure. The irreversible opening of the mitochondrial permeability transition pore (PTP), in response to increased matrix Ca2+ and reactive oxygen species, is invariably associated with the death of the cell. Indeed, the PTP appears to be a universal mediator of all forms of regulated necrosis. Despite the importance of the PTP, its molecular identity was unknown until the recent discovery by a member of this network implicating the mitochondrial FOF1-ATP synthase. Although accumulating experimental evidence from network members suggests a central role for PTP opening in ischemia reperfusion (I/R) injury and in heart failure, clinical data remain equivocal, largely due to lack of suitable inhibitors of the PTP.  Members of the Targeting Mitochondria to Treat Heart Disease network have identified novel PTP inhibitors through chemical screening. They propose to use this technology to improve our understanding of how molecular signalling leads to cell death through the opening of the PTP. Further, they plan to test whether PTP inhibition, preventing the opening of the pore and perhaps with it the death of the cell, has clinical utility in heart failure, or in I/R injury.