Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: a potential role for mitochondrial proteases

Abstract

As part of this thematic series on mitochondria in cell death, we would like to review our data on: (1) the role of the mitochondrial permeability transition (MPT) in hepatocyte necrosis during cholestasis; and (2) the concept that endogenous mitochondrial protease activity may lead to the MPT. Many chronic human liver diseases are characterized by cholestasis, an impairment in bile flow. During cholestasis an accumulation of toxic hydrophobic bile salts in the hepatocyte causes necrosis. We tested the hypothesis that toxic hydrophobic bile salt, glycochenodeoxycholate (GCDC), causes hepatocyte necrosis by inducing the MPT. GCDC induces a rapid, cyclosporin A-sensitive MPT. The hydrophilic bile salt, ursodeoxycholate (UDCA), prevents the GCDC-induced MPT and hepatocyte necrosis providing an explanation for its beneficial effect in human liver disease. We have also demonstrated that the calcium-dependent MPT is associated with an increase in calpain-like protease activity and inhibited by calpain inhibitors. In an experimental model of cholestasis, mitochondrial calpain-like protease activity increases 1.6-fold. We propose for the first time that activation of mitochondrial proteases may initiate the MPT and cell necrosis during cholestasis.

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

“…However, at lower concentrations (: 50 mM), bile acids may alter cell function by interfering with intracellular signaling mechanisms (Rust et al, 2000) and mitochondrial membrane permeability (Gores et al, 1998;Rolo et al, 2000). Regardless, cholestasis due to accumulation of bile acids has been thought to reflect the direct cytotoxicity of the individual bile acids (Kaplan, 1994).…”

“…In order to provide new insights into the understanding of the effects of therapeutic bile acids, in vitro studies have been done. Several reports described a role for the putative beneficial effect of UDCA exerted at the level of mitochondrial function, where UDCA prevents the impairment of mitochondrial function induced by toxic bile acids (Gores et al, 1998;Rodrigues et al, 1998). It has also been reported that UDCA could exert a cytoprotective action related to oxidative injury and antioxidant systems (Mitsuyoshi et al, 1999).…”

“…This accumulation of cytotoxic bile acids is thought to cause hepatocyte necrosis contributing to the pathogenesis of the cholestatic disease process and the development of liver cirrhosis and liver failure (Kaplan, 1994). Mechanisms implicated in the toxicity of bile acids include stimulation of lipid peroxidation (Sokol et al, 1993) and induction of mitochondrial dysfunction (Schaffner et al, 1971;Krahenbuhl et al, 1992;Gores et al, 1998;Rolo et al, 2000).…”

Nitric Oxide Ameliorates Hydrophobic Bile Acid-induced Apoptosis in Isolated Rat Hepatocytes by Non-mitochondrial Pathways

“…Induction of the MPT, characterized by large amplitude swelling and loss of the electrochemical potential across the inner mitochondrial membrane (8,9), leads to release of cytochrome c and apoptosis-inducing factor into cytosol, activating downstream caspases and cellular apoptosis (10). The role of the MPT in bile acid-induced hepatocyte necrosis and apoptosis has recently been established (11)(12)(13)(14)(15). Evidence from several laboratories indicates that stimulation of the MPT by bile acids is commensurate with increased generation of ROS (7,11,14,15) and that oxidative modification of the MPT pore may mediate its opening (16).…”

Regional Loss of the Mitochondrial Membrane Potential in the Hepatocyte Is Rapidly Followed by Externalization of Phosphatidylserines at That Specific Site during Apoptosis

“…Moreover, the mitochondria are a source of a number of the Bcl-2 family members and, in lymphoid cells, of the apoptosis inducing factor, a protein associated with opening of the pore and induction of apoptosis (10). Other mitochondrial factors that are associated with liver apoptosis in vivo are proteases that are released during cholestasis (11). Finally several studies showed that after induction of apoptosis mitochondria release cytochrome c (12), which is associated with opening of the mitochondrial pore (13).…”