The effect of chronic alcohol consumption on mitochondrial calcium handling in hepatocytes.
The effect of chronic alcohol consumption on mitochondrial calcium handling in hepatocytes.
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慢性饮酒对肝细胞中线粒体钙处理的影响。
DOI：
10.1042/bcj20160255
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发表时间：
2016-11-01
期刊：
影响因子：
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通讯作者：
Gaspers LD
中科院分区：
文献类型：
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作者：
Wang G;Mémin E;Murali I;Gaspers LD
在人类和动物模型中，过量饮酒后普遍观察到肝脏线粒体的损伤。急性酒精治疗已被证明刺激钙（Ca2+）从肝细胞的内部存储的释放。预期胞质Ca 2+的所得增加由邻近线粒体累积，这可能导致线粒体Ca 2+过载和损伤。我们的数据表明，总的和游离的线粒体基质Ca2+的水平，确实，升高的肝细胞分离酒精喂养的大鼠相比，他们对喂养的控制同窝出生。在透性化肝细胞中，线粒体Ca 2+摄取率在慢性酒精喂养后显著增加，而线粒体Ca 2+流出率则降低。线粒体Ca2+处理的变化可以解释为上调的线粒体Ca2+单向转运体和环孢菌素A敏感的Ca2+转运途径的损失。在完整的细胞中，与对照组相比，酒精诱导的线粒体Ca 2+增加以较慢的速度下降，导致基质Ca 2+的升高时间更长。此外，治疗与次最大浓度的钙动员激素显着增加了线粒体活性氧（ROS）的水平在肝细胞中的酒精喂养的大鼠，但不影响ROS水平的控制。线粒体Ca2+处理的变化预计缓冲和减弱急性酒精暴露或激素刺激诱导的细胞溶质Ca2+增加。然而，线粒体Ca2+处理的这些改变也可能导致胞质Ca2+增加期间的Ca2+过载，这可能刺激线粒体ROS的产生，从而导致酒精诱导的肝损伤。
The damage to liver mitochondria is universally observed in both humans and animal models after excessive alcohol consumption. Acute alcohol treatment has been shown to stimulate calcium (Ca2+) release from internal stores in hepatocytes. The resultant increase in cytosolic Ca2+ is expected to be accumulated by neighboring mitochondria, which could potentially lead to mitochondrial Ca2+ overload and injury. Our data indicate that total and free mitochondrial matrix Ca2+ levels are, indeed, elevated in hepatocytes isolated from alcohol-fed rats compared with their pair-fed control littermates. In permeabilized hepatocytes, the rates of mitochondrial Ca2+ uptake were substantially increased after chronic alcohol feeding, whereas those of mitochondrial Ca2+ efflux were decreased. The changes in mitochondrial Ca2+ handling could be explained by an up-regulation of the mitochondrial Ca2+ uniporter and loss of a cyclosporin A-sensitive Ca2+ transport pathway. In intact cells, hormone-induced increases in mitochondrial Ca2+ declined at slower rates leading to more prolonged elevations of matrix Ca2+ in the alcohol-fed group compared with controls. Moreover, treatment with submaximal concentrations of Ca2+-mobilizing hormones markedly increased the levels of mitochondrial reactive oxygen species (ROS) in hepatocytes from alcohol-fed rats, but did not affect ROS levels in controls. The changes in mitochondrial Ca2+ handling are expected to buffer and attenuate cytosolic Ca2+ increases induced by acute alcohol exposure or hormone stimulation. However, these alterations in mitochondrial Ca2+ handling may also lead to Ca2+ overload during cytosolic Ca2+ increases, which may stimulate the production of mitochondrial ROS, and thus contribute to alcohol-induced liver injury.