Heat stress prevents mitochondrial injury in ATP-depleted renal epithelial cells
Heat stress prevents mitochondrial injury in ATP-depleted renal epithelial cells
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DOI：
10.1152/ajpcell.00517.2001
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发表时间：
2002-09-01
影响因子：
5.5
通讯作者：
Borkan, SC
中科院分区：
文献类型：
--
作者：
Li, F;Mao, HP;Borkan, SC
导致细胞死亡的事件和在 ATP 耗尽期间负责细胞保护的应激蛋白仍然难以捉摸。我们假设暴露于代谢抑制剂会损害线粒体，使促凋亡蛋白渗漏到细胞质中，并表明热应激诱导的 hsp72 积累可防止线粒体膜损伤。为了测试这些假设，在不存在培养基葡萄糖的情况下，用氰化钠和 2-脱氧-D-葡萄糖暂时耗尽肾上皮细胞的 ATP。 ATP 消耗的恢复与细胞色素 c 和凋亡诱导因子 (AIF) 释放到胞浆中有关，这些促凋亡蛋白定位于线粒体间膜空间。伴随着线粒体细胞色素 c 泄漏，观察到 caspase 3 活性增加了七到八倍。在对照组中，短暂暴露于代谢抑制剂后，状态 III 线粒体呼吸减少了 30%。先前的热应激保留了线粒体 ATP 的产生，并显着减少了细胞色素 c 的释放和 caspase 3 的激活。尽管细胞色素 c 释放较少，但先前的热应激增加了细胞色素 c 和 hsp72 之间的结合。本研究表明，线粒体损伤伴随着暴露于代谢抑制剂。通过减少线粒体外膜损伤并与细胞色素 c 复合，hsp72 可以抑制 caspase 激活和随后的细胞凋亡。
The events that precipitate cell death and the stress proteins responsible for cytoprotection during ATP depletion remain elusive. We hypothesize that exposure to metabolic inhibitors damages mitochondria, allowing proapoptotic proteins to leak into the cytosol, and suggest that heat stress-induced hsp72 accumulation prevents mitochondrial membrane injury. To test these hypotheses, renal epithelial cells were transiently ATP depleted with sodium cyanide and 2-deoxy-D-glucose in the absence of medium dextrose. Recovery from ATP depletion was associated with the release into the cytosol of cytochrome c and apoptosis-inducing factor (AIF), proapoptotic proteins that localize to the intermitochondrial membrane space. Concomitant with mitochondrial cytochrome c leak, a seven- to eightfold increase in caspase 3 activity was observed. In controls, state III mitochondrial respiration was reduced by 30% after transient exposure to metabolic inhibitors. Prior heat stress preserved mitochondrial ATP production and significantly reduced both cytochrome c release and caspase 3 activation. Despite less cytochrome c release, prior heat stress increased binding between cytochrome c and hsp72. The present study demonstrates that mitochondrial injury accompanies exposure to metabolic inhibitors. By reducing outer mitochondrial membrane injury and by complexing with cytochrome c, hsp72 could inhibit caspase activation and subsequent apoptosis.