Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions

The mitochondrial permeability transition (mPT) describes a Ca2+-dependent and cyclophilin D (CypD)-facilitated increase of innermitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel,the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outermitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However,transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrialbioenergetics and rapid Ca2+ efflux. Since its discovery decades ago, intensive efforts have been made to identify the exact pore-formingstructure of the mPT. Both the adenine nucleotide translocase (ANT) and, more recently, the mitochondrial F1FO (F)-ATP synthase dimers,monomers or c-subunit ring alone have been implicated. Here we share the insights of several key investigators with different perspectiveswho have pioneered mPT research. We critically assess proposed models for the molecular identity of the mPTP and the mechanismsunderlying its opposing roles in the life and death of cells. We provide in-depth insights into current controversies, seeking to achieve adegree of consensus that will stimulate future innovative research into the nature and role of the mPTP.