Progressive stages of mitochondrial destruction caused by cell toxic bile salts

https://doi.org/10.1016/j.bbamem.2013.05.007Get rights and content
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Highlights

  • Bile salt mediated direct mitochondrio-toxicity is bile salt species-, dose- and time-dependent.

  • Toxic bile salts paradoxically inverse MMP-depletion and MPT-onset.

  • The mitochondrial destruction by toxic bile salts is sequential.

  • The mitochondrial membrane protein ANT is a target for toxic bile salts.

  • The destruction mode provides explanation for the apoptosis/necrosis switch in vivo.

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.

Abbreviations

ANT
adenine nucleotide translocator
Cyt C
cytochrome C
Cys A
cyclosporine A
FCCP
carbonylcyanide-p-(trifluoromethoxy) phenyl-hydrazone
GCDCA
glycochenodeoxycholic acid
IM
inner membrane
MβCD
methyl-β-cyclodextrin
MMP
mitochondrial membrane potential
MOMP
mitochondrial outer membrane rupture
MPT
mitochondrial permeability transition
4-MUP
4-methylumbelliferyl phosphate
OD
optical density
OM
outer membrane
PC
phosphatidylcholine
Rh123
rhodamine 123
ROS
reactive oxygen species
TCDCA
taurochenodeoxycholic acid
TUDCA
tauroursodeoxycholic acid
VDAC
voltage-dependent anion channel
ZE-FFE
zone electrophoresis in a free flow electrophoresis device

Keywords

Mitochondria
Bile salts
Cholestasis
Mitochondrial permeability transition
Liver

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