TITLE

Mechanisms regulating cytochrome c release in pancreatic mitochondria

AUTHOR(S)
I V Odinokova
PUB. DATE
March 2009
SOURCE
Gut;Mar2009, Vol. 58 Issue 3, p431
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
BACKGROUND: Mechanisms of acinar cell death in pancreatitis are poorly understood. Cytochrome c release is a central event in apoptosis in pancreatitis. Here, we assessed the regulation of pancreatic cytochrome c release by Ca2+, mitochondrial membrane potential (ΔΨm), and reactive oxygen species (ROS), the signals involved in acute pancreatitis. We used both isolated rat pancreatic mitochondria and intact acinar cells hyperstimulated with cholecystokinin-8 (CCK-8; in vitro model of acute pancreatitis). RESULTS: Micromolar amounts of Ca2+depolarised isolated pancreatic mitochondria through a mechanism different from the "classical" (ie, liver) mitochondrial permeability transition pore (mPTP). In contrast with liver, Ca2+-induced mPTP opening caused a dramatic decrease in ROS and was not associated with pancreatic mitochondria swelling. Importantly, we found that Ca2+-induced depolarisation inhibited cytochrome c release from pancreatic mitochondria, due to blockade of ROS production. As a result, Ca2+exerted two opposite effects on cytochrome c release: Ca2+per se stimulated the release, whereas Ca2+-induced depolarisation inhibited it. This dual effect caused a non-monotonous dose-dependence of cytochrome c release on Ca2+. In intact acinar cells, cytochrome c release, caspase activation and apoptosis were all stimulated by ROS and Ca2+, and inhibited by depolarisation, corroborating the findings on isolated pancreatic mitochondria. CONCLUSIONS: These data implicate ROS as a key mediator of CCK-induced apoptotic responses. The results indicate a major role for mitochondria in the effects of Ca2+ and ROS on acinar cell death. They suggest that the extent of apoptosis in pancreatitis is regulated by the interplay between ROS, ΔΨm and Ca2+. Stabilising mitochondria against loss of ΔΨm may represent a strategy to mitigate the severity of pancreatitis.
ACCESSION #
36473408

 

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