The mitochondrial permeability transition pore and ischemia-reperfusion injury

Abstract

Mitochondrial dysfunction is an underlying cause of ischemia-reperfusion injury. In particular, ischemic injury induces dramatic increases in mitochondrial permeability, thereby instigating a chain of events that leads to both apoptotic and necrotic cardiomyocyte death. The mitochondrial permeability transition (MPT) pore, a large, non-specific channel that spans the inner mitochondrial membrane, is known to mediate the lethal permeability changes that initiate mitochondrial-driven cardiomyocyte death. The purpose of this review is to focus on the role of the MPT pore in ischemia-reperfusion injury, the mechanisms involved, and, in particular, what we do and do not know regarding the pore's molecular composition.

Fig. 1

Molecular models for the mitochondrial permeability transition (MPT) pore. On the left is shown the original model for the MPT pore, consisting of the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane (OMM), the adenine nucleotide translocase (ANT) in the inner mitochondrial membrane (IMM), and cyclophilin-D (CypD) in the matrix. However, as shown on the right, if we apply recent findings in gene-targeted mice the model becomes very different. VDAC is no longer part of the model, ANT is now more of a regulatory protein, and only CypD remains as an established component. Consequently, the identity of the pore-forming protein(s) remains unknown

Fig. 2

The three main models for how pro-death Bcl-2 proteins induce apoptogen release from mitochondria: (1) pro-death members simply form their own protein-permeant pore; (2) pro-death Bcl-2 proteins interact with VDAC to form a protein-permeant channel that specifically permeabilizes the outer membrane; or (3) pro-death Bcl-2 proteins bind to and evoke opening of the MPT pore. Although there is considerable evidence supporting and refuting, respectively, the first two models, the role of the MPT pore in this process remains controversial