Two modes of activation of the permeability transition pore: the role of mitochondrial cyclophilin.
Mitochondria possess an inner membrane channel, the permeability transition pore, which is inhibited by cyclosporin A (CsA) and by matrix protons. As suggested recently by our laboratory, pore closure by these inhibitors may be due to dissociation of mitochondrial cyclophilin (CyP-M), a matrix peptidyl-prolyl-cis-trans isomerase, from its putative binding site on the pore. Unbinding of CyP-M would follow a CsA-dependent or proton-dependent change in conformation of the CyP-M molecule. It is interesting that upon binding of CsA the enzymatic activity of CyP-M is inhibited, but it is not clear whether this event plays a role in pore inhibition. Here we report experiments designed to further test the role of CyP-M in pore function. Our results indicate that CyP-M-dependent and independent mechanisms of pore activation may exist, and that the peptidylprolyl-cis-trans-isomerase activity of CyP-M is not necessarily involved in pore modulation by CyP-M.
Scorrano
L
L
C.N.R. Unit for the Study of Biomembranes, University of Padova, Italy.
Nicolli
A
A
Basso
E
E
Petronilli
V
V
Bernardi
P
P
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D051381:Rats
D007473:Ion Channels; D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase