Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?
Cyclosporin A (CsA) inhibits the mitochondrial permeability transition (MPT), but not always. To characterize the CsA-sensitive and -insensitive MPT, rat liver mitochondria were exposed to low and high doses of various MPT inducers. Mitochondrial swelling, cyclophilin D membrane binding and permeability transition (PT) pore diameter were measured. The results indicate two conductance modes for the PT pore: one activated by Ca(2+) and inhibited by CsA and Mg(2+) and the other unregulated. We propose a new model of pore formation and gating in which PT pores form by aggregation of misfolded integral membrane proteins damaged by oxidant and other stresses. Chaperone-like proteins initially block conductance through these misfolded protein clusters; however, increased Ca(2+) opens these regulated PT pores, an effect blocked by CsA. When protein clusters exceed chaperones available to block conductance, unregulated pore opening occurs.
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Lihua
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Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, CB#7090, 236 Taylor Hall, Chapel Hill, NC 27599-7090, USA.
Lemasters
John J
JJ
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004553:Electric Conductivity; D015640:Ion Channel Gating; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D010539:Permeability; D017510:Protein Folding; D051381:Rats
D000081406:Peptidyl-Prolyl Isomerase F; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018832:Molecular Chaperones; D016572:Cyclosporine; D021983:Cyclophilins; D008274:Magnesium; D002118:Calcium