Differential susceptibility of subsarcolemmal and intermyofibrillar mitochondria to apoptotic stimuli
Differential susceptibility of subsarcolemmal and intermyofibrillar mitochondria to apoptotic stimuli
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DOI：
10.1152/ajpcell.00031.2005
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发表时间：
2005-10-01
影响因子：
5.5
通讯作者：
Hood, DA
中科院分区：
文献类型：
--
作者：
Adhihetty, PJ;Ljubicic, V;Hood, DA
细胞凋亡可以通过活性氧（ROS）诱导的促凋亡因子细胞色素c和凋亡诱导因子（AIF）的线粒体释放来诱发。由于骨骼肌是由两个线粒体亚组分，居住在不同的亚细胞区域，我们研究了肌膜下（SS）和肌原纤维间（IMF）线粒体的凋亡易感性。SS和IMF线粒体表现出剂量依赖性释放的蛋白质响应H2 O2（0，25，50，和100 μ M）。然而，IMF线粒体对H2 O2更敏感，释放的细胞色素c和AIF的量分别是SS线粒体的2.5倍和10倍。这一发现与IMF线粒体中蛋白质释放通道（线粒体通透性转换孔（mtPTP））的开放率（吸光度降低的最大速率，V-max）增加44%（P < 0.05）相一致。与SS线粒体相比，IMF线粒体的关键mtPTP组分电压依赖性阴离子通道和亲环素D的表达分别高出47%（P < 0.05）和60%（0.05 < P < 0.1），细胞色素c含量沿着增加3倍，但AIF水平相似。尽管SS线粒体对H2 O2诱导的释放的敏感性较低，但与IMF线粒体相比，SS线粒体的Bcl-2/Bcl-2比值高10倍（P < 0.05），ROS产生率高2.7倍，膜电位高约2倍。亚组分之间的抗氧化酶Mn 2 +-超氧化物歧化酶的表达相似。因此，SS和IMF线粒体之间的mtPTP的不同蛋白质组成和功能有助于响应ROS的细胞色素c和AIF的差异释放。考虑到肌纤维内IMF线粒体的相对高比例，当存在凋亡刺激时，该亚组分可能在诱导凋亡中最重要，最终导致肌萎缩和肌纤维萎缩。
Apoptosis can be evoked by reactive oxygen species (ROS)-induced mitochondrial release of the proapoptotic factors cytochrome c and apoptosis-inducing factor (AIF). Because skeletal muscle is composed of two mitochondrial subfractions that reside in distinct subcellular regions, we investigated the apoptotic susceptibility of subsarcolemmal (SS) and intermyofibrillar ( IMF) mitochondria. SS and IMF mitochondria exhibited a dose-dependent release of protein in response to H2O2 ( 0, 25, 50, and 100 mu M). However, IMF mitochondria were more sensitive to H2O2 and released a 2.5-fold and 10-fold greater amount of cytochrome c and AIF, respectively, compared with SS mitochondria. This finding coincided with a 44% (P < 0.05) greater rate of opening ( maximum rate of absorbance decrease, V-max) of the protein release channel, the mitochondrial permeability transition pore (mtPTP), in IMF mitochondria. IMF mitochondria also exhibited a 47% (P < 0.05) and 60% (0.05 < P < 0.1) greater expression of the key mtPTP component voltage-dependent anion channel and cyclophilin D, respectively, along with a threefold greater cytochrome c content, but similar levels of AIF compared with SS mitochondria. Despite a lower susceptibility to H2O2-induced release, SS mitochondria possessed a 10-fold greater Bax-to-Bcl-2 ratio (P < 0.05), a 2.7-fold greater rate of ROS production, and an approximately twofold greater membrane potential compared with IMF mitochondria. The expression of the antioxidant enzyme Mn2+-superoxide dismutase was similar between subfractions. Thus the divergent protein composition and function of the mtPTP between SS and IMF mitochondria contributes to a differential release of cytochrome c and AIF in response to ROS. Given the relatively high proportion of IMF mitochondria within a muscle fiber, this subfraction is likely most important in inducing apoptosis when presented with apoptotic stimuli, ultimately leading to myonuclear decay and muscle fiber atrophy.