Progressive stages of mitochondrial destruction caused by cell toxic bile salts

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• 作者：Sabine Schulz ; Sabine Schmitt ; Ralf Wimmer ; Michaela Aichler ; Sabine Eisenhofer ; Josef Lichtmannegger ; Carola Eberhagen ; Renate Artmann ; Ferenc Tookos ; Axel Walch ; Daniel Krappmann ; Catherine Brenner ; Christian Rust ; Hans Zischka
• 关键词：ANT ; adenine nucleotide translocator ; Cyt C ; cytochrome C ; Cys A ; cyclosporine A ; FCCP ; carbonylcyanide-p-(trifluoromethoxy) phenyl-hydrazone ; GCDCA ; glycochenodeoxycholic acid ; IM ; inner membrane ; M¦ÂCD ; methyl-¦Â-cyclodextrin ; MMP ; mitochondrial membran
• 刊名：Biochimica et Biophysica Acta (BBA)/Biomembranes
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：1828
• 期：9
• 页码：2121-2133
• 全文大小：1429 K

文摘

The cell-toxic bile salt glycochenodeoxycholic acid (GCDCA) and taurochenodeoxycholic acid (TCDCA) are responsible for hepatocyte demise in cholestatic liver diseases, while tauroursodeoxycholic acid (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.