Progressive stages of mitochondrial destruction caused by cell toxic bile salts
Progressive stages of mitochondrial destruction caused by cell toxic bile salts
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DOI：
10.1016/j.bbamem.2013.05.007
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发表时间：
2013-09-01
影响因子：
3.4
通讯作者：
Zischka, Hans
中科院分区：
文献类型：
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作者：
Schulz, Sabine;Schmitt, Sabine;Zischka, Hans
细胞毒性胆汁盐甘鹅去氧胆酸 (GCDCA) 和牛磺鹅去氧胆酸 (TCDCA) 是胆汁淤积性肝病中肝细胞死亡的原因，而牛磺熊去氧胆酸 (TUDCA) 被认为具有保肝作用。我们证明了胆汁盐的直接线粒体毒性，它会消耗线粒体膜电位并诱导线粒体通透性转变（MPT）。胆盐介导的破坏机制与钙（MPT 诱导剂原型）显着不同。细胞毒性胆汁盐最初与线粒体外膜结合。随后，内边界膜的结构瓦解。并且只有在此之后，MPT 才会被诱导。这种渐进性破坏以剂量和时间依赖性方式发生。我们证明 GCDCA 和 TCDCA（而非 TUDCA）优先透化含有线粒体膜蛋白 ANT 的脂质体，这一过程类似于整个线粒体中的 MPT 诱导。这表明 ANT 是有毒胆盐的决定性目标之一。据我们所知，这是第一份揭示细胞毒性胆汁盐导致线粒体破坏的连续步骤的报告。 (C) 2013 Elsevier B.V. 保留所有权利。
The cell-toxic bile salt glycochenodeoxycholic acid (GCDCA) and taurochenodeoxycholic acid (TCDCA) are responsible for hepatocyte demise in cholestatic liver diseases, while tauroursodeoxycholic add (TUDCA) is regarded hepatoprotective. We demonstrate the direct mitochondrio-toxicity of bile salts which deplete the mitochondrial membrane potential and induce the mitochondrial permeability transition (MPT). The bile salt mediated mechanistic mode of destruction significantly differs from that of calcium, the prototype MPT inducer. Cell-toxic bile salts initially bind to the mitochondrial outer membrane. Subsequently, the structure of the inner boundary membrane disintegrates. And it is only thereafter that the MPT is induced. This progressive destruction occurs in a dose- and time-dependent way. We demonstrate that GCDCA and TCDCA, but not TUDCA, preferentially permeabilize liposomes containing the mitochondrial membrane protein ANT, a process resembling the MPT induction in whole mitochondria. This suggests that ANT is one decisive target for toxic bile salts. To our knowledge this is the first report unraveling the consecutive steps leading to mitochondrial destruction by cell-toxic bile salts. (C) 2013 Elsevier B.V. All rights reserved.