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Progressive stages of mitochondrial destruction caused by cell toxic bile salts.
Biochim. Biophys. Acta-Biomembr. 1828, 2121-2133 (2013)
The cell-toxic bile salts 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mitochondria; Bile salts; Cholestasis; Mitochondrial permeability transition; Liver; Permeability Transition Pore ; Rat-liver Mitochondria ; Saccharomyces-cerevisiae Mitochondria ; Adenine-nucleotide Translocase ; Free-flow Electrophoresis ; Outer-membrane ; Contact Sites ; Inner Membrane ; Cyclosporine-a ; Benzodiazepine-receptor
ISSN (print) / ISBN 0005-2736
Quellenangaben Volume: 1828, Issue: 9, Pages: 2121-2133
Reviewing status Peer reviewed