Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?
Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?
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DOI：
10.1016/s0014-5793(01)03314-2
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发表时间：
2002-02-13
期刊：
影响因子：
3.5
通讯作者：
Lemasters, JJ
中科院分区：
文献类型：
--
作者：
He, LH;Lemasters, JJ
环孢菌素A（CsA）抑制线粒体渗透性转变（MPT），但并不总是如此。为了表征CsA敏感和不敏感的MPT，大鼠肝线粒体暴露于低剂量和高剂量的各种MPT诱导剂。测量线粒体肿胀、亲环素D膜结合和渗透性转变（PT）孔径。结果表明，PT孔有两种电导模式：一种是Ca ~（2+）激活，CsA和Mg ~（2+）抑制，另一种是不受调节。我们提出了一个新的模型孔形成和门控PT孔形成的聚集错误折叠的完整的膜蛋白被氧化剂和其他应力损坏。伴侣样蛋白最初通过这些错误折叠的蛋白质簇阻断电导;然而，增加的Ca 2+打开这些受调节的PT孔，CsA阻断了这种作用。当蛋白质簇超过可用于阻断电导的分子伴侣时，发生不受调节的孔开放。(C)2002年欧洲生物化学学会联合会。由Elsevier Science B. V.出版，版权所有。
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. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.