SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.
SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.
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DOI：
10.1016/j.molcel.2015.08.009
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发表时间：
2015-10-01
期刊：
影响因子：
16
通讯作者：
Madesh M
中科院分区：
文献类型：
--
作者：
Shanmughapriya S;Rajan S;Hoffman NE;Higgins AM;Tomar D;Nemani N;Hines KJ;Smith DJ;Eguchi A;Vallem S;Shaikh F;Cheung M;Leonard NJ;Stolakis RS;Wolfers MP;Ibetti J;Chuprun JK;Jog NR;Houser SR;Koch WJ;Elrod JW;Madesh M
线粒体通透性转换是指线粒体通透性转换孔（PTP）突然打开，导致线粒体膜电位（Δ Km）耗散，ATP产生减少，细胞死亡的现象。已经提出了几种遗传候选物来形成PTP复合物，但是核心组分是未知的。我们使用基于RNAi的筛选确定了痉挛性截瘫7（SPG 7）在Ca 2+和ROS诱导的PTP开放中的必要和保守的作用。SPG 7的缺失导致更高的线粒体Ca 2+，类似于亲环素D（CypD，PPIF）敲低，在Ca 2+和ROS胁迫期间具有持续的Δ m。生化分析表明PTP是由VDAC、SPG 7和CypD组成的异源寡聚复合物。沉默或破坏SPG 7-CypD结合可防止Ca 2+和ROS诱导的Δ Δ μ m去极化和细胞死亡。这项研究确定了一种普遍表达的IMM整合蛋白SPG 7，作为PTP在OMM和IMM接触位点的核心组分。
Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex however the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca2+ and ROS-induced PTP opening using RNAi based screening. Loss of SPG7 resulted in higher mitochondrial Ca2+, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca2+ and ROS stress. Biochemical analyses revealed that the PTP is a hetero-oligomeric complex composed of VDAC, SPG7 and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+ and ROS-induced ΔΨm depolarization and cell death. This study identifies a ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.