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Schulz, S. ; Schmitt, S. ; Wimmer, R.* ; Aichler, M. ; Eisenhofer, S. ; Lichtmannegger, J. ; Eberhagen, C. ; Artmann, R.* ; Toókos, F. ; Walch, A.K. ; Krappmann, D. ; Brenner-Jan, C.* ; Rust, C.* ; Zischka, H.

Progressive stages of mitochondrial destruction caused by cell toxic bile salts.

Biochim. Biophys. Acta-Biomembr. 1828, 2121-2133 (2013)
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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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0005-2736
e-ISSN 1879-2642
Zeitschrift Biochimica et Biophysica Acta - Biomembranes
Quellenangaben Band: 1828, Heft: 9, Seiten: 2121-2133 Artikelnummer: , Supplement: ,
Verlag Elsevier
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)
Research Unit Analytical Pathology (AAP)
Institute of Pathology (PATH)
Institute of Computational Biology (ICB)
Research Unit Signaling and Translation (SAT)
POF Topic(s) 30203 - Molecular Targets and Therapies
30205 - Bioengineering and Digital Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-505200-003
G-500390-001
G-500300-001
G-503800-001
G-509800-002
PubMed ID 23685124
DOI 10.1016/j.bbamem.2013.05.007
WOS ID WOS:000322353900013
Scopus ID 84879234547
Erfassungsdatum 2013-05-22
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