Mitochondria impairment is a critical event in anthrax lethal toxin-induced cytolysis of murine macrophages
Mitochondria impairment is a critical event in anthrax lethal toxin-induced cytolysis of murine macrophages
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DOI：
10.4161/cc.5.1.2283
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发表时间：
2006-01-01
期刊：
影响因子：
4.3
通讯作者：
Brojatsch, J
中科院分区：
文献类型：
--
作者：
Alileche, A;Squires, RC;Brojatsch, J
炭疽致死毒素(LT)介导的细胞杀伤的许多早期事件已被描述，包括LT的摄取和MAPKK的裂解。然而，LT致死的关键下游事件仍有待确定。在这项研究中，我们提出了LT导致小鼠J774A.1巨噬细胞线粒体功能障碍的证据，其表现为线粒体膜电位和SDH活性的持续下降。超微结构分析揭示了LT诱导的线粒体肿胀，进一步支持了这一点。在LT处理的巨噬细胞中，线粒体损伤和细胞溶解是由蛋白酶体控制的：即使在膜扰动之前立即加入蛋白酶体抑制剂，也能恢复线粒体的活性并将细胞从细胞溶解中拯救出来。与蛋白酶体抑制剂类似，KCl也有效地阻止LT介导的细胞溶解，即使在后期添加之后也是如此。然而，KCl不能阻止线粒体损伤，尽管它排除了与LT诱导的细胞溶解有关的事件。这些事件包括ATP水平和泛素化蛋白的急剧下降，揭示了它们是LT杀伤中的附属物。我们的研究表明，蛋白酶体和钾控制LT诱导的线粒体功能障碍和膜扰动，这是LT杀伤的关键事件。
Numerous early events in anthrax lethal toxin (LT)-mediated cell killing have been described, including uptake of LT and MAPKK cleavage. However, critical downstream events in LT killing remain to be identified. In this study we present evidence that LT causes mitochondrial dysfunction in murine J774A.1 macrophages, as indicated by a continuous drop in both mitochondrial membrane potential and SDH activity. This was further supported by ultrastructural analysis revealing LT-induced swelling of mitochondria. Mitochondrial impairment and cytolysis were controlled by proteasomes in LT-treated macrophages: proteasome inhibitors restored mitochondrial activity and rescued cells from cytolysis, even when added immediately prior to membrane perturbation. Similar to proteasome inhibitors, KCl also efficiently blocked LT-mediated cytolysis, even after late addition. However, KCl did not prevent mitochondrial impairment, though it precluded events linked to LT-induced cytolysis. These events included a precipitous drop in ATP levels and ubiquitinated proteins, revealing that they are epiphenomena in LT killing. Our studies suggest that proteasomes and potassium control LT-induced mitochondrial dysfunction and membrane perturbation, key events in LT killing.