TY - JOUR
T1 - Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis
T2 - A potential role for mitochondrial proteases
AU - Gores, Gregory J.
AU - Miyoshi, Hideyuki
AU - Botla, Ravi
AU - Aguilar, Humberto I.
AU - Bronk, Steven F.
N1 - Funding Information:
The skillful secretarial assistance of Sara Erickson is gratefully acknowledged. This work was supported by grants from the National Institutes of Health (DK 41876), the Gainey Foundation (St. Paul, MN) and by the Mayo Foundation (Rochester, MN).
PY - 1998/8/10
Y1 - 1998/8/10
N2 - 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. Copyright (C) 1998 Elsevier Science B.V.
AB - 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. Copyright (C) 1998 Elsevier Science B.V.
KW - Bile duct-ligated rat
KW - Bile salt
KW - Cbz-Leu-Leu-Tyr-CHN
KW - Cytoprotection
KW - Ursodeoxycholate
KW - tert-Butylhydroperoxide
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U2 - 10.1016/S0005-2728(98)00111-X
DO - 10.1016/S0005-2728(98)00111-X
M3 - Article
C2 - 9714791
AN - SCOPUS:0032504695
SN - 0005-2728
VL - 1366
SP - 167
EP - 175
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
IS - 1-2
ER -