pH-dependent nonlysosomal proteolysis contributes to lethal anoxic injury of rat hepatocytes

S. F. Bronk, G. J. Gores

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Our aim was to test the hypothesis that pH-dependent nonlysosomal proteolysis is a key mechanism culminating in lethal anoxic injury of rat hepatocytes. Although lysosomal proteolysis was suppressed during anoxia, total nonlysosomal proteolysis was increased twofold compared with aerobic controls. Extracellular acidosis inhibited total nonlysosomal proteolysis and improved cell survival during anoxia. Indeed, we found a direct highly significant linear relationship between cell death and total nonlysosomal proteolysis as modulated by changes in the extracellular pH (r = 0.99, P < 0.01). Glycolytic generation of ATP from fructose during anoxia suppressed total nonlysosomal proteolysis and improved cell survival. An increase in a pH-dependent calpain-like protease activity was also identified during anoxia, but calpain-like protease activity only accounted for 16% of total nonlysosomal protease activity. In addition, the calpain protease inhibitor Cbz-Leu-Leu-Tyr-CHN2 only partially protected against cell killing despite complete inhibition of calpain-like protease activity. These data suggest that pH-dependent total nonlysosomal proteolysis contributes to lethal cell injury during anoxia. However, calpain protease activity only partially contributes to total nonlysosomal protease activity and cell death.

Original languageEnglish (US)
Pages (from-to)G744-G751
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume264
Issue number4 27-4
StatePublished - Jan 1 1993

Keywords

  • 3- methyladenine
  • acidosis
  • adenosine triphosphate
  • calpains
  • lysosomal proteolysis
  • monensin

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'pH-dependent nonlysosomal proteolysis contributes to lethal anoxic injury of rat hepatocytes'. Together they form a unique fingerprint.

  • Cite this