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

Gregory J. Gores, Hideyuki Miyoshi, Ravi Botla, Humberto I. Aguilar, Steven F. Bronk

Research output: Contribution to journalArticle

112 Scopus citations

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. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)167-175
Number of pages9
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1366
Issue number1-2
DOIs
StatePublished - Aug 10 1998

Keywords

  • Bile duct-ligated rat
  • Bile salt
  • Cbz-Leu-Leu-Tyr-CHN
  • Cytoprotection
  • Ursodeoxycholate
  • tert-Butylhydroperoxide

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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