Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane

Abstract

The mitochondrial permeability transition pore allows solutes with a m.w. approximately less than 1500 to equilibrate across the inner membrane. A closed pore is favored by cyclosporin A acting at a high-affinity site, which may be the matrix space cylophilin isozyme. Early results obtained with cyclosporin A analogs and metabolites support this hypothesis. Inhibition by cyclosporin does not appear to require inhibition of calcineurin activity; however, it may relate to inhibition of cyclophilin peptide bond isomerase activity. The permeability transition pore is strongly regulated by both the membrane potential (delta psi) and delta pH components of the mitochondrial protonmotive force. A voltage sensor which is influenced by the disulfide/sulhydryl state of vicinal sulfhydryls is proposed to render pore opening sensitive to delta psi. Early results indicate that this sensor is also responsive to membrane surface potential and/or to surface potential gradients. Histidine residues located on the matrix side of the inner membrane render the pore responsive to delta pH. The pore is also regulated by several ions and metabolites which act at sites that are interactive. There are many analogies between the systems which regulate the permeability transition pore and the NMDA receptor channel. These suggest structural similarities and that the permeability transition pore belongs to the family of ligand gated ion channels.

Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis

“…The MPT induction is strongly regulated by both Dc and DpH components of the mitochondrial protonmotive force, divalent cations and different metabolites [38], in addition to the thiol redox status of cysteine residues in the vicinity of the voltage sensor of the pore that determines the probability of MPT induction [18,19,30]. Moreover, the MPT possesses at least two redox-sensitive sites, one of them in equilibrium with GSH of mitochondrial matrix and another that can be directly activated by ROS [30].…”

Calcineurin and mitochondrial function in glutamate‐induced neuronal cell death

“…CsA is a high-affinity inhibitor of a pore in the matrixdelimiting mitochondrial membrane [15,34]. Pore opening or permanence of the pore in an open state is favored by Ca 2+ or depolarization.…”

Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator

“…We and others have shown that pro-apoptotic Bcl-2 family members (Bax, Bak, Bid, and Bik) induce apoptotic changes in isolated mitochondria that are prevented by Bcl-2 and Bcl-x L (JuÈ rgensmeier et al, 1998;Narita et al, 1998;Eskes et al, 1998;Shimizu and Tsujimoto, 2000). Although there seems to be controversy, it has been shown that Bax-and Bak-induced mitochondrial changes are mediated by a polyprotein channel called the permeability transition (PT) pore (Narita et al, 1998;Marzo et al, 1998), which is considered to form at sites of contact between the mitochondrial inner and outer membranes and to consist of mitochondrial porin (also called the voltage-dependent anion channel, VDAC), the adenine nucleotide translocator (ANT), cyclophilin D, and some other molecules (reviewed by Bernardi et al, 1994;Zoratti and Szabo , 1995). VDAC is an abundant outer mitochondrial membrane protein that forms a large (53 nm) voltage-gated pore when incorporated into planar lipid bilayers (reviewed by Colombini, 1989).…”