Molecular, homeostatic, and structural coincidences in the mPTP formation. Hypothetical scheme to illustrate how only a few of the otherwise abundant pore-building constituents form the mPTP. Although mitochondria are full of the main (most established) PT pore components, ANT and F₁F₀-ATPase, they transform to mPTP only at the right place and right time under specific circumstances. Without listing all components, some of the main coincidence factors proposed to drive the mPTP formation are shown in the scheme: the pore component at an OMM–IMM contact site may be exposed to high local [Ca²⁺] next to MCUC for an extended time. The location is close to a cristae junction and the involved crista is depicted with locally altered ΔΨm (either hyperpolarization, producing more ROS, or depolarization as mPTP sensitizers). Recruitment of cyclophilin D (CypD) from the matrix is required as well as inputs from OMM-resident proteins, particularly the relatively low (compared with VDAC) number of oligomerized Bax/Bak. Besides (or as a result of) the coinciding factors, the ‘chosen apo-constituents’ will undergo the necessary transformation to form mPTP.