Kokoszka Jason E, Waymire Katrina G, Levy Shawn E, Sligh James E, Cai Jiyang, Jones Dean P, MacGregor Grant R, Wallace Douglas C
Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California 92697, USA.
Nature. 2004 Jan 29;427(6973):461-5. doi: 10.1038/nature02229.
A sudden increase in permeability of the inner mitochondrial membrane, the so-called mitochondrial permeability transition, is a common feature of apoptosis and is mediated by the mitochondrial permeability transition pore (mtPTP). It is thought that the mtPTP is a protein complex formed by the voltage-dependent anion channel, members of the pro- and anti-apoptotic BAX-BCL2 protein family, cyclophilin D, and the adenine nucleotide (ADP/ATP) translocators (ANTs). The latter exchange mitochondrial ATP for cytosolic ADP and have been implicated in cell death. To investigate the role of the ANTs in the mtPTP, we genetically inactivated the two isoforms of ANT in mouse liver and analysed mtPTP activation in isolated mitochondria and the induction of cell death in hepatocytes. Mitochondria lacking ANT could still be induced to undergo permeability transition, resulting in release of cytochrome c. However, more Ca2+ than usual was required to activate the mtPTP, and the pore could no longer be regulated by ANT ligands. Moreover, hepatocytes without ANT remained competent to respond to various initiators of cell death. Therefore, ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation.
线粒体内膜通透性的突然增加，即所谓的线粒体通透性转换，是细胞凋亡的一个共同特征，由线粒体通透性转换孔（mtPTP）介导。据认为，mtPTP是一种蛋白质复合物，由电压依赖性阴离子通道、促凋亡和抗凋亡BAX - BCL2蛋白家族成员、亲环素D以及腺嘌呤核苷酸（ADP/ATP）转位体（ANTs）组成。后者将线粒体ATP与胞质ADP进行交换，并与细胞死亡有关。为了研究ANTs在mtPTP中的作用，我们通过基因手段使小鼠肝脏中的两种ANT同工型失活，并分析了分离线粒体中mtPTP的激活情况以及肝细胞中细胞死亡的诱导情况。缺乏ANT的线粒体仍可被诱导发生通透性转换，导致细胞色素c释放。然而，激活mtPTP需要比平常更多的Ca2+，并且该孔不再受ANT配体的调节。此外，没有ANT的肝细胞仍然能够对各种细胞死亡启动因子做出反应。因此，ANTs不是mtPTP的必需结构成分，尽管它们确实有助于其调节。
