Signal transduction to the permeability transition pore

Abstract 

The permeability transition pore (PTP) is an inner mitochondrial membrane channel that has been thoroughly characterized functionally, yet remains an elusive molecular entity. The best characterized PTP-regulatory component, cyclophilin (CyP) D, is a matrix protein that favors pore opening. CyP inhibitors, CyP-D null animals, and in situ PTP readouts have established the role of PTP as an effector mechanism of cell death, and the growing definition of PTP signalling mechanisms. This review briefly covers the functional features of the PTP and the role played by its dysregulation in disease pathogenesis. Recent progress on PTP modulation by kinase/phosphatase signal transduction is discussed, with specific emphasis on hexokinase and on the Akt-ERK-GSK3 axis, which might modulate the PTP through CyP-D phosphorylation.

Abbreviations: Aβ, amyloid beta, ANT, adenine nucleotide translocator, CsA, cyclosporin A, CyP-D, cyclophilin D, ERK, extracellular signal regulated kinase, GPCRs, G protein coupled receptors, GSK3, glycogen synthase kinase 3, HK, hexokinase, Hsp90, heat shock protein 90, IMM, inner mitochondrial membrane, OMM, outer mitochondrial membrane, P_i, phosphate anion, PiC, phosphate carrier, PINK1, PTEN induced kinase 1, PKC, protein kinase C, PKG, protein kinase G, PP2A, protein phosphatase 2A, PP2B, protein phosphatase 2B, PP2Cm, mitochondrial protein phosphatase 2C, PT, permeability transition, PTP, permeability transition pore, RISK, reperfusion injury salvage kinase, ROS, reactive oxygen species, RTKs, receptor tyrosine kinases, SHP-1, SH2-containing tyrosine phosphatase 1, TRAP-1, tumor necrosis factor receptor-associated protein 1, VDAC, voltage-dependent anion channel

Keywords: Permeability transition pore, Cyclophilin D, Apoptosis, Channel, Kinase, Chaperone