Precht T A, Phelps R A, Linseman D A, Butts B D, Le S S, Laessig T A, Bouchard R J, Heidenreich K A
Department of Pharmacology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver, CO, USA.
Cell Death Differ. 2005 Mar;12(3):255-65. doi: 10.1038/sj.cdd.4401552.
Cerebellar granule neurons (CGNs) require depolarization for their survival in culture. When deprived of this stimulus, CGNs die via an intrinsic apoptotic cascade involving Bim induction, Bax translocation, cytochrome c release, and caspase-9 and -3 activation. Opening of the mitochondrial permeability transition pore (mPTP) is an early event during intrinsic apoptosis; however, the precise role of mPTP opening in neuronal apoptosis is presently unclear. Here, we show that mPTP opening acts as an initiating event to stimulate Bax translocation to mitochondria. A C-terminal (alpha9 helix) GFP-Bax point mutant (T182A) that constitutively localizes to mitochondria circumvents the requirement for mPTP opening and is entirely sufficient to induce CGN apoptosis. Collectively, these data indicate that the major role of mPTP opening in CGN apoptosis is to trigger Bax translocation to mitochondria, ultimately leading to cytochrome c release and caspase activation.
小脑颗粒神经元（CGNs）在培养中存活需要去极化。当缺乏这种刺激时，CGNs通过涉及Bim诱导、Bax易位、细胞色素c释放以及caspase-9和-3激活的内在凋亡级联反应而死亡。线粒体通透性转换孔（mPTP）的开放是内在凋亡过程中的早期事件；然而，mPTP开放在神经元凋亡中的确切作用目前尚不清楚。在此，我们表明mPTP开放作为一个起始事件来刺激Bax易位至线粒体。一个组成性定位于线粒体的C末端（α9螺旋）GFP-Bax点突变体（T182A）规避了对mPTP开放的需求，并且完全足以诱导CGN凋亡。总体而言，这些数据表明mPTP开放在CGN凋亡中的主要作用是触发Bax易位至线粒体，最终导致细胞色素c释放和caspase激活。
