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亲环蛋白D的缺失揭示了线粒体通透性转换在细胞死亡中的关键作用。

Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.

作者信息

Baines Christopher P, Kaiser Robert A, Purcell Nicole H, Blair N Scott, Osinska Hanna, Hambleton Michael A, Brunskill Eric W, Sayen M Richard, Gottlieb Roberta A, Dorn Gerald W, Robbins Jeffrey, Molkentin Jeffery D

机构信息

Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

出版信息

Nature. 2005 Mar 31;434(7033):658-62. doi: 10.1038/nature03434.

Abstract

Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.

摘要

线粒体在介导凋亡性和坏死性细胞死亡过程中发挥着关键作用。线粒体通透性转换(mPT)会导致线粒体肿胀、外膜破裂以及凋亡介质的释放。mPT孔被认为由腺嘌呤核苷酸转位酶、电压依赖性阴离子通道和环孢素D(Ppif基因产物)组成,环孢素D是一种位于线粒体基质中的脯氨酰异构酶。在此,我们培育出了心脏中缺乏Ppif的小鼠以及过表达环孢素D的小鼠。Ppif基因敲除小鼠在体内可免受缺血/再灌注诱导的细胞死亡,而过表达环孢素D的小鼠则表现出线粒体肿胀和自发性细胞死亡。从Ppif基因敲除小鼠的肝脏、心脏和大脑中分离出的线粒体在体外对线粒体肿胀和通透性转换具有抗性。此外,从Ppif基因敲除小鼠中分离出的原代肝细胞和成纤维细胞在很大程度上可免受钙离子过载和氧化应激诱导的细胞死亡。然而,Bcl-2家族成员诱导的细胞死亡并不依赖于环孢素D,Ppif基因敲除的成纤维细胞也不能免受星形孢菌素或肿瘤坏死因子-α诱导的死亡。因此,环孢素D和线粒体通透性转换是介导钙离子和氧化损伤诱导的细胞死亡所必需的,但不是Bcl-2家族成员调节的细胞死亡所必需的。

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