Under conditions of mitochondrial calcium overload, especially when accompanied by oxidative stress, elevated phosphate concentrations and adenine nucleotide depletion, a non-specific pore, the mitochondrial permeability transition pore (MPTP), opens in the inner mitochondrial membrane. One major consequence of MPTP opening is that the inner mitochondrial membrane no longer maintains a barrier to protons which leads to dissipation of the proton motive force.The resulting uncoupling of oxidative phosphorylation not only prevents mitochondria from making ATP, but the proton-translocating ATPase goes into reverse. This means that within any cell the “open” mitochondria hydrolyse ATP generated by glycolysis and any “closed” mitochondria, leading to ATP depletion and bioenergetic failure of the myocyte. A second consequence of MPTP opening is that all small molecular weight molecules equilibrate across the inner membrane, including cofactors and ions. 
In view of its central role in reperfusion injury, the MPTP has become an obvious target for cardioprotection. Such as hexokinase, creatine kinase and the anti- and pro-apoptotic proteins Bcl-2 and Bax may also associate with the MPTP. In cancer cells, glycogen synthase kinase 3β (GSK3β) has been shown to phosphorylate VDAC1, reduce hexokinase II (HK-II) binding to mitochondria and inhibit MPTP opening. HK binding to VDAC may also play an important role in regulating MPTP opening in the heart. Thus cardioprotection by ischemic preconditioning, is associated with an increase in HK-II binding to subsequently isolated mitochondria. Akt may phosphorylate HK-II bound to mitochondria leading to inhibition of MPTP opening.


1.Mnatsakanyan N, et al. J Bioenerg Biomembr. 2017;49(1):13–25.