Signal transduction to the permeability transition pore

Abstract

a b s t r a c tThe 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. Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. General features of the permeability transition poreThe permeability transition pore (PTP) is a voltage-and Ca 2+ -dependent, cyclosporin A (CsA)-sensitive, high conductance channel, whose opening leads to permeabilization of the inner mitochondrial membrane (IMM) to solutes with molecular masses up to 1500 Da. A prolonged PTP opening has major consequences on energy metabolism and cell viability. Mitochondria depolarize due to equilibration of the proton gradient and the initial uncoupling is followed by release of matrix pyridine nucleotides resulting in respiratory inhibition and generation of reactive oxygen species (ROS) via the direct transfer of electrons to molecular oxygen. Oxidative phosphorylation and ATP synthesis cease, and the F 0 F 1 ATP synthase starts working in reverse, hydrolyzing ATP generated by glycolysis or by residual functional mitochondria. As a result, a bioenergetic failure rapidly occurs [1]. Moreover, ions and solutes with molecular mass below the pore size equilibrate across the IMM, inducing disruption of metabolic gradients and release of the Ca 2+ stored in the matrix. The colloidal osmotic pressure exerted by the high protein concentration in the matrix causes its swelling. Inner membrane cristae unfold and eventually may disrupt the outer membrane, leading to release of intermembrane proteins, including pro-apoptotic factors [2]. Thus, PTP opening prompts the demise of the cell, either through apoptosis (if enough ATP is present to fuel caspase activity), or through necrosis (that follows loss of Ca 2+ homeostasis and mitochondrial dysfunction). The mode of cell demise could be necrotic when the permeability transition (PT) occurs in a fraction of mitochondria sufficient to cause ATP depletion. A more limited number of permeabilized mitochondria would lead to release of proapoptotic factors, and ATP production by the residual healthy mitochondria would be enough to support apoptosis execution. In a cell, a subpopulation of mitochondria may have a lower threshold for opening (e.g. those spatially closer to the triggering signal) and therefore open the ...

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…A major mitochondrial death pathway is elicited by apoptotic Bcl-2 family proteins such as Bax and Bak and/or the mitochondrial permeability transition pore (mPTP), a mega channel formed at the mitochondrial inner membrane. [86][87][88][89][90] Activated Bax/Bak forms a pore at the mitochondrial outer membrane (MOM) resulting in a release of apoptotic factors from the intra-membrane space. 86,91 MitoHK-II antagonizes apoptotic Bcl-2 family proteins and thereby protects cells against apoptotic stimuli.…”

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

“…These and other observations provide evidence that ANT is located in the contact sites of mitochondrial membranes in complex with VDAC and other proteins, such as creatine kinase and CypD (Vyssokikh and Brdiczka, 2003). However, despite the use of multiple methodologies, such as co-immunoprecipation, proteomic analysis, co-purification, genetic validation, the identity and the number of PTPC components are still elusive (Zoratti et al, 2005;Brenner and Grimm, 2006;Halestrap, 2009;Rasola et al, 2010) and it remains to be seen whether ANT and VDAC are the main components of the PTPC or just regulators or accessory PTPC proteins. Notably, using isolated mitochondria from mice knock-out for ANT 1/2 or, VDAC1, or VDAC3, or VDAC1/3 and CypD, a permeability transition response to the classical inducer Ca 2 þ was monitored and results suggested a limited role for these proteins in MMP (for discussion, see Rasola et al, 2010).…”

“…Interestingly, the PiC has been proposed recently to function as the IM channel of PTPC (Leung et al, 2008), but this awaits genetic demonstration. Finally, an attractive possibility might be that the composition of this pore varies depending on the tissue as well as the pathophysiological state (Halestrap, 2009, Rasola et al, 2010. Irrespective of these premises, Brustovetsky and Klingenberg (1996) used electrophysiological approaches to show that pure native ANT could be converted into a large channel by Ca 2 þ following reconstitution into liposomes (Brustovetsky and Klingenberg, 1996).…”

Role of protein kinase C and mitochondrial permeability transition pore in the neuroprotective effect of ceramide in ischemia-induced cell death

“…One potential target is the mitochondrial permeability transition pore (mPTP). This pore is a multiprotein complex formed across the two mitochondrial membranes [8]. The mPTP opening in ischemia/recovery may act as a trigger for apoptosis.…”

“…In this case, closing of mPTP could avoid the cellular death. Nevertheless, a controlled and reversible opening of the mPTP can be related to protection [8,9].…”