Bile acids affect liver mitochondrial bioenergetics: Possible relevance for cholestasis therapy

It has been pointed out that intracellular accumulation of bile acids cause hepatocyte injury in cholestatic disease process. This study was aimed to test if cytotoxicity of these compounds is mediated through mitochondria dy sfunction. Bile acids effects on isolated rat liver mitochondrial were anal yzed by monitoring changes in membrane potential and mitochondrial respirat ion, as well as alterations in H+ membrane permeability and mitochondrial p ermeability transition pore induction. Increasing concentrations of the bil e acids litocholic (LCA), deoxycholic (DCA), ursodeoxycholic (UDCA), chenod eoxycholic (CDCA), glycochenodeoxycholic (GCDC), or taurochenodeoxycholic ( TCDC) decrease transmembrane potential (Delta Psi) developed upon succinate energization. These compounds also decreased state 3 respiration and enhan ced state 4. We have also demonstrated that the observed concentration-depe ndent stimulation of state 4 by LCA, DCA, CDCA, TCDC, and GCDC, is associat ed with an enhanced permeability of mitochondria to H+. Addition of LCA, DC A, CDCA, TCDC, GCDC, and UDCA to mitochondria energized with succinate resu lted in a dose-dependent membrane depolarization and stimulation of mitocho ndrial permeability transition. Tauroursodeoxycholate (TUDC) elicited no si gnificant effect on succinate-supported mitochondrial bioenergetics. In con trast, in the presence of glycoursodeoxycholic (GUDC), Delta Psi increases as a function of bile salt concentration. The results of this investigation demonstrate that at toxicologically relevant concentrations, most but not all bile acids alter mitochondrial bioenergetics, so impairment of mitochon drial function can be clinically relevant for patients with cholestasis.