title: Progressive stages of mitochondrial destruction caused by cell toxic bile salts.
abstract: 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.
authors.affiliation: Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schulz
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmitt
authors.forename: Ralf
authors.initials: R
authors.lastname: Wimmer
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Sabine
authors.initials: S
authors.lastname: Eisenhofer
authors.forename: Josef
authors.initials: J
authors.lastname: Lichtmannegger
authors.forename: Carola
authors.initials: C
authors.lastname: Eberhagen
authors.forename: Renate
authors.initials: R
authors.lastname: Artmann
authors.forename: Ferenc
authors.initials: F
authors.lastname: Tookos
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Christian
authors.initials: C
authors.lastname: Rust
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity*; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000737:chemistry; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000226:Mitochondrial ADP, ATP Translocases / Q000819:agonists* / Q000302:isolation & purification; D033681:Mitochondrial Membrane Transport Proteins / Q000819:agonists / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009206:Myocardium / Q000737:chemistry; D051381:Rats; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology* / Q000633:toxicity; D050994:Voltage-Dependent Anion Channels / Q000737:chemistry / Q000302:isolation & purification
chemical_list: D008081:Liposomes; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D050994:Voltage-Dependent Anion Channels; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D005999:Glycochenodeoxycholic Acid; D000226:Mitochondrial ADP, ATP Translocases
keywords: 4-MUP; 4-methylumbelliferyl phosphate; ANT; Bile salts; Cholestasis; Cys A; Cyt C; FCCP; GCDCA; IM; Liver; MMP; MOMP; MPT; Mitochondria; Mitochondrial permeability transition; MβCD; OD; OM; PC; ROS; Rh123; TCDCA; TUDCA; VDAC; ZE-FFE; adenine nucleotide translocator; carbonylcyanide-p-(trifluoromethoxy) phenyl-hydrazone; cyclosporine A; cytochrome C; glycochenodeoxycholic acid; inner membrane; methyl-β-cyclodextrin; mitochondrial membrane potential; mitochondrial outer membrane rupture; mitochondrial permeability transition; optical density; outer membrane; phosphatidylcholine; reactive oxygen species; rhodamine 123; taurochenodeoxycholic acid; tauroursodeoxycholic acid; voltage-dependent anion channel; zone electrophoresis in a free flow electrophoresis device