Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?

来自 dx.doi.org

喜欢 0

阅读量：

104

作者：

L He，JJ Lemasters

展开

摘要：

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.

展开

关键词：

Rat liver mitochondrion Cyclophilin D Cyclosporin A Calcium Amphipathic peptide Oxidant chemical ANT, adenine nucleotide translocator COX IV, cytochrome c oxidase subunit IV CsA, cyclosporin A CypD, cyclophilin D DTT, dithiothreitol GSH, reduced glutathione MPT, mitochondrial permeability transition PEG, polyethylene glycol PhAsO, phenylarsine oxide PT, permeability transition VDAC, voltage-dependent anion channel