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

FEBS Letters

He, Lihua¹  Lemasters, John J¹ 

[1]Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, CB#7090, 236 Taylor Hall, Chapel Hill, NC 27599-7090, USA

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;   

DOI  :  10.1016/S0014-5793(01)03314-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 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 Ca²⁺ and inhibited by CsA and Mg²⁺ 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 Ca²⁺ opens these regulated PT pores, an effect blocked by CsA. When protein clusters exceed chaperones available to block conductance, unregulated pore opening occurs.

【 授权许可】

Unknown