In one model (A), the PT pore is composed of ANT from the inner membrane (IM), CypD from the matrix, VDAC from the outer membrane (OM) and other proteins, including hexokinase (HK), creatine kinase (CK) and Bax, a proapoptotic Bcl2 family member. Ca2+, inorganic phosphate (Pi), ROS and oxidized pyridine nucleotides NAD(P)+ and glutathione (GSSG) promote PT pore opening, whereas CsA, Mg2+ and pH less than 7 inhibit opening. In an alternative model (B), PT pores form from misfolding and aggregation of damaged mitochondrial membrane proteins at hydrophilic surfaces facing the hydrophobic membrane bilayer. CypD and other chaperones bind to the nascent PT pores and block conductance of solutes through the aqueous channels formed by the protein clusters. High Ca2+ opens these regulated channels acting through CypD, an effect blocked by CsA. As misfolded protein clusters exceeds the number of chaperones available to regulate them, constitutively open unregulated channels form that are not inhibited by CsA.