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.

Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties

“…Effi cient mitochondria labeling by Rho-123 on hepatocytes was observed ( Fig. 4B, E ), while DCA-NBD Supplemental Material can be found at: ( 20 ). Previous studies have also identifi ed changes in average membrane fl uidity of isolated mitochondria after exposure to toxic bile acids ( 44 ).…”

“…Cytotoxic bile acids have been shown to induce cell death through multiple pathways, depending on their concentrations ( 3,4 ), but the corresponding mechanism of action of these molecules is still highly ambiguous and a matter of much debate, as the target of these molecules has recently been alternatively suggested to be the plasma membrane ( 17 ) or the MOM ( 20 ). Our previous studies have demonstrated that at physiologically active concentrations, cytotoxic bile acids have the potential to modulate the structure of lipid membranes, but only for certain lipidic compositions, namely, in the presence of low concentrations of Chol ( 14 ).…”

“…In this case, cytotoxic bile acids could act directly on mitochondrial membranes, either through a change of mitochondrial membrane properties or through a direct increase in the permeability of mitochondrial membranes. A recent study put forward compelling evidence suggesting that cytotoxic bile acids detach the inner boundary membrane from the mitochondrial outer membrane (MOM) and, fi nally, induce MPT, likely at the remaining contact sites ( 20 ).…”

“…( 14,17 ) have confi rmed that apoptosis-inducing bile acids are able to modulate lipid membrane fl uidity, suggesting that their physiological activity could be associated with this effect. Different organelles have been anticipated as targets for cytotoxic bile acids, namely, the plasma membrane ( 17 ) and the mitochondria ( 20 ). Our approach to elucidate this issue was to carry out a quantitative evaluation of the impact of physiologically active DCA concentrations on the membrane order of both these organelles.…”

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

“…Recent work has focused on the role of both bile acids in cell signaling and sterile inflammation in the pathophysiology of cholestasis. Thus, reducing the intracellular content and cytotoxicity of bile acids (and other potentially toxic cholephilic compounds that accumulate after secretory failure) is very important for the prevention of cholestatic liver injury [2][3][4] .…”