RECENT PROGRESS ON REGULATION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE - A CYCLOSPORINE-SENSITIVE PORE IN THE INNER MITOCHONDRIAL-MEMBRANE
RECENT PROGRESS ON REGULATION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE - A CYCLOSPORINE-SENSITIVE PORE IN THE INNER MITOCHONDRIAL-MEMBRANE
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DOI：
10.1007/bf00762735
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发表时间：
1994-10-01
影响因子：
3
通讯作者：
PFEIFFER, DR
中科院分区：
文献类型：
--
作者：
BERNARDI, P;BROEKEMEIER, KM;PFEIFFER, DR
线粒体通透性转换孔允许溶质具有分子量。小于或接近 1500 以平衡内膜。作用于高亲和力位点的环孢菌素 A 有利于封闭的孔，该位点可能是基质空间亲环素同工酶。用环孢菌素 A 类似物和代谢物获得的早期结果支持了这一假设。环孢菌素的抑制似乎不需要抑制钙调磷酸酶活性；然而，它可能与亲环蛋白肽键异构酶活性的抑制有关。渗透性转换孔受到线粒体质子动力的膜电位 (Delta psi) 和 Delta pH 分量的强烈调节。提出了一种受邻位巯基的二硫化物/巯基状态影响的电压传感器，以使孔隙开口对 Delta psi 敏感。早期结果表明，该传感器还对膜表面电位和/或表面电位梯度敏感。位于内膜基质侧的组氨酸残基使孔对 Delta pH 做出响应。孔还受到在相互作用位点起作用的几种离子和代谢物的调节。调节通透性转换孔和 NMDA 受体通道的系统之间有许多相似之处。这些表明结构相似，并且渗透性过渡孔属于配体门控离子通道家族。
The mitochondrial permeability transition pore allows solutes with a m.w. less than or similar to 1500 to equilibrate across the inner membrane. A closed pore is favored by cyclosporin A acting at a high-affinity site, which may be the matrix space cylophilin isozyme. Early results obtained with cyclosporin A analogs and metabolites support this hypothesis. Inhibition by cyclosporin does not appear to require inhibition of calcineurin activity; however, it may relate to inhibition of cyclophilin peptide bond isomerase activity. The permeability transition pore is strongly regulated by both the membrane potential (Delta psi) and Delta pH components of the mitochondrial protonmotive force. A voltage sensor which is influenced by the disulfide/sulhydryl state of vicinal sulfhydryls is proposed to render pore opening sensitive to Delta psi. Early results indicate that this sensor is also responsive to membrane surface potential and/or to surface potential gradients. Histidine residues located on the matrix side of the inner membrane render the pore responsive to Delta pH. The pore is also regulated by several ions and metabolites which act at sites that are interactive. There are many analogies between the systems which regulate the permeability transition pore and the NMDA receptor channel. These suggest structural similarities and that the permeability transition pore belongs to the family of ligand gated ion channels.