Mitochondrial permeability transition, F1FO‐ATPase and calcium: an enigmatic triangle

The permeability transition pore (PTP) is a mysterious structure that induces cell death by increasing the permeability of the inner mitochondrial membrane (IMM) to ions and soluble molecules. In 2015, the F1FO‐ATPase was identified as being involved in forming the PTP in eukaryotes [1]. Two hypotheses were put forward to explain the mechanism of PTP opening, both of which involve the mitochondrial F1FO‐ATPase: the channel forms within the c ‐ring [2] or results from the conformational changes of F1FO‐ATPase dimers [3]. F1FO‐ATPase is a multisubunit enzyme at the cristae edges of the IMM that either synthesizes (forward reaction) or hydrolyses ATP (reverse reaction) in the catalytic hydrophilic F1 domain while translocating H+ through the c ‐ring in the hydrophobic FO domain. The first hypothesis by Alavian and colleagues proposes that the PTP channel is created within the c ‐ring of the FO subunit by Ca2+‐dependent extrusion of the extrinsic F1 domain from the membrane‐embedded FO domain of the enzyme [2]. However, two points remain obscure: the occurrence of cyclophilin D in the basic structure of the “ c ‐ring channel” and the F1 domain detachment from the FO domain, which usually occurs only under extreme conditions, for example, high urea concentration. However, downregulation with siRNA and dephosphorylation of c ‐ring subunits support a role in PTP opening [1]. In addition, a mitochondrial water‐permeable channel has been proposed based on a de novo complex composed …