Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové, Charles University in Prague, 500 01 Hradec Kralove I, Czech Republic.
Biometals. 2010 Apr;23(2):339-54. doi: 10.1007/s10534-010-9302-8. Epub 2010 Feb 12.
Increased intracellular free zinc concentrations are associated with activation of several stress signaling pathways, specific organelle injury and final cell death. In the present work we examined the involvement of mitochondria and lysosomes and their crosstalk in free zinc-induced cell demise. We report that treatment of cervical tumor Hep-2 cells with zinc pyrithione leads to an early appearance of cytoplasmic zinc-specific foci with corresponding accumulation of zinc first in mitochondria and later in lysosomes. Concomitant with these changes, upregulation of expression of metallothionein II A gene as well as the increased abundance of its protein occurs. Moreover, zinc activates p53 and its dependent genes including Puma and Bax and they contribute to an observed loss of mitochondrial membrane potential and activation of apoptosis. Conversely, lysosomal membrane permeabilization and its promoted cleavage of Bid occurs in a delayed manner in treated cells and their effect on decrease of mitochondrial membrane potential is limited. The use of specific inhibitors as well as siRNA technology suggest a crucial role of MT-IIA in trafficking of free zinc into mitochondria or lysosomes and regulation of apoptotic or necrotic cell demise.
细胞内游离锌浓度的增加与几种应激信号通路的激活、特定细胞器损伤和最终细胞死亡有关。在本工作中，我们研究了线粒体和溶酶体及其在游离锌诱导细胞死亡中的相互作用。我们报告说，用吡啶硫酮锌处理宫颈肿瘤 Hep-2 细胞会导致细胞质中出现锌特异性焦点，同时锌首先在线粒体中积累，然后在溶酶体中积累。伴随着这些变化，金属硫蛋白 IIA 基因的表达上调以及其蛋白的丰度增加。此外，锌激活 p53 及其依赖的基因，包括 Puma 和 Bax，它们导致观察到的线粒体膜电位丧失和细胞凋亡的激活。相反，溶酶体膜通透性及其促进的 Bid 裂解在处理细胞中延迟发生，并且它们对线粒体膜电位降低的影响是有限的。使用特异性抑制剂和 siRNA 技术表明，MT-IIA 在游离锌向线粒体或溶酶体的运输以及调节细胞凋亡或坏死性细胞死亡中起着关键作用。
