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首页> 外文期刊>Molecular and Cellular Biology >Susceptibility of Lysosomes to Rupture Is a Determinant for Plasma Membrane Disruption in Tumor Necrosis Factor Alpha-Induced Cell Death
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Susceptibility of Lysosomes to Rupture Is a Determinant for Plasma Membrane Disruption in Tumor Necrosis Factor Alpha-Induced Cell Death

机译：溶酶体破裂的易感性是肿瘤坏死因子α诱导的细胞死亡中质膜破坏的决定因素。

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Since a release of intracellular contents can induce local inflammatory responses, mechanisms that lead to loss of plasma membrane integrity in cell death are important to know. We showed previously that deficiency of the plasma membrane Ca2+ ATPase 4 (PMCA4) in L929 cells impaired tumor necrosis factor alpha (TNF-α)-induced enlargement of lysosomes and reduced cell death. The lysosomal changes can be determined by measuring the total volume of intracellular acidic compartments per cell (VAC), and we show here that inhibition of the increase in VAC due to PMCA4 deficiency not only reduced cell death but also converted TNF-α-induced cell death from a process involving disruption of the plasma membrane to a cell demise with a nearly intact plasma membrane. The importance of the size of lysosomes in determining plasma membrane integrity during cell death was supported by the observations that chemical inhibitors that reduce VAC also reduced the plasma membrane disruption induced by TNF-α in wild-type L929 cells, while increases in VAC due to genetic mutation, senescence, cell culture conditions, and chemical inhibitors all changed the morphology of cell death from one with an originally nearly intact plasma membrane to one with membrane disruption in a number of different cells. Moreover, the ATP depletion-mediated change from apoptosis to necrosis is also associated with the increases of VAC. The increase in lysosomal size may due to intracellular self-digestion of dying cells. Big lysosomes are easy to rupture, and the release of hydrolytic enzymes from ruptured lysosomes can cause plasma membrane disruption.
机译：由于细胞内内容物的释放可以诱导局部炎症反应，因此在细胞死亡中导致质膜完整性丧失的机制非常重要。我们以前表明，L929细胞中质膜Ca 2 + ATPase 4（PMCA4）的缺乏损害了肿瘤坏死因子α（TNF-α）诱导的溶酶体扩张并降低了细胞死亡。溶酶体的变化可以通过测量每个细胞的细胞内酸性区室（VAC）的总体积来确定，我们在这里表明由于PMCA4缺乏而抑制VAC的增加不仅减少了细胞死亡，而且还转化了TNF-α诱导的细胞因涉及质膜几乎完整的细胞膜破裂至细胞死亡的过程而死亡。溶酶体大小对确定细胞死亡过程中质膜完整性的重要性得到了以下观察结果的支持：降低VAC的化学抑制剂还减少了野生型L929细胞中TNF-α诱导的质膜破坏，而VAC由于遗传突变，衰老，细胞培养条件和化学抑制剂都改变了细胞死亡的形态，从最初具有几乎完整的质膜的细胞死亡变成了在许多不同细胞中被膜破坏的细胞死亡。此外，ATP耗竭介导的从凋亡到坏死的变化也与VAC的增加有关。溶酶体大小的增加可能是由于垂死细胞的细胞内自我消化。大的溶酶体很容易破裂，破裂的溶酶体中释放的水解酶会导致质膜破裂。

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