Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS-dependent pathway
Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS-dependent pathway
复制标题
DOI：
10.1038/sj.bjp.0706069
复制
发表时间：
2005-02-01
影响因子：
7.3
通讯作者：
Jordán, J
中科院分区：
文献类型：
--
作者：
Fernandez-Gomez, FJ;Galindo, MF;Jordán, J
本文研究了线粒体复合体II抑制剂丙二酸酯对其主要靶点线粒体的影响丙二酸盐诱导线粒体电位塌陷、线粒体肿胀、细胞色素c （Cyt c）释放和消耗脑分离线粒体中谷胱甘肽（GSH）和烟酰胺腺嘌呤二核苷酸辅酶（NAD(P)H）的储存虽然添加丙二酸盐后线粒体电位崩溃几乎立即发生，但在用药15分钟前线粒体肿胀并不明显。后一种效应被环孢素A （CSA）、钌红（RR）、镁、过氧化氢酶、谷胱甘肽和维生素e阻断。添加到SH-SY5Y细胞培养物中的丙二酸盐显著降低细胞活力，同时释放Cyt c，降低GSH和NAD(P) H浓度。这些作用在过表达Bcl-xL.5的SH-SY5Y细胞中不明显当用丁硫氨酸亚砜降低GSH浓度时，Bcl-xL过表达对细胞的保护作用不再明显综上所述，所有这些数据都表明，丙二酸盐会导致线粒体电位的快速崩溃和活性氧的产生，从而破坏线粒体的抗氧化能力，导致线粒体肿胀。因此，进一步的渗透性过渡开孔和随后的促凋亡因子（如Cyt c）的释放可能至少在一定程度上导致丙二酸盐诱导的毒性。
1 Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion.2 Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria.3 Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E.4 Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD( P) H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL.5 When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore.6 Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity.