Mitochondrial permeability transition pore and Cardioprotection against ischemia-reperfusion injury

Abstract

Opening of mitochondrial permeability transition pore (mPTP) was found to have a critical role in cell death from ischemia/reperfusion (I/R) injury experimentally in the late 1980's. Thereafter, tremendous efforts have been made to define the molecular composition of mPTP and underlying mechanisms of its opening. mPTP opening, so far, has been demonstrated with the conformational changes of the mitochondrial protein components including cyclophilin-D, adenine nucleotide translocase, and voltage-dependent anion channel, which were induced by the modification of the levels of Ca2+, phosphate, mitochondrial membrane potential, intracellular pH and adenine nucleotide. At present, genetic modulation of the expression of protein components are being used in the investigation of its properties, presenting novel mechanisms of mPTP opening, including phosphate carrier. For therapeutic intervention, cyclosporin A and its analogues were first to be demonstrated to inhibit the opening of mPTP, affecting cyclophilin-D. There are numerous pharmacological substances that have direct or indirect effects on mPTP opening, including bongkrekic acid, reactive oxygen species scavengers, calcium channel blockers, and Na+/H + exchanger-1 inhibitors, but only cyclosporin A was clinically tried to limit the myocardial infarction. Conditioning interventions, ischemic or anesthetic, have also been shown to be effective in limiting the detrimental effects of I/R injury. These interventions are commonly related to specific receptors on cell membrane and then signal transduction pathway consisting of many protein kinases, which eventually lead to mitochondria. And being presented are experimental evidences that inhibition of mPTP opening is a primary mechanism of these conditioning interventions. In conclusion, mPTP opening is now presented as primary mechanism and therapeutic target of I/R injury, but precise mechanism and standardized treatment method are needed to be clarified.