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2009 ; 58
(3
): 431-42
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Mechanisms regulating cytochrome c release in pancreatic mitochondria
#MMPMID18596195
Odinokova IV
; Sung KF
; Mareninova OA
; Hermann K
; Evtodienko Y
; Andreyev A
; Gukovsky I
; Gukovskaya AS
Gut
2009[Mar]; 58
(3
): 431-42
PMID18596195
show ga
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 Ca(2+),
mitochondrial membrane potential (Delta Psi m), 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 Ca(2+) depolarised isolated pancreatic mitochondria through
a mechanism different from the "classical" (ie, liver) mitochondrial permeability
transition pore (mPTP). In contrast with liver, Ca(2+)-induced mPTP opening
caused a dramatic decrease in ROS and was not associated with pancreatic
mitochondria swelling. Importantly, we found that Ca(2+)-induced depolarisation
inhibited cytochrome c release from pancreatic mitochondria, due to blockade of
ROS production. As a result, Ca(2+) exerted two opposite effects on cytochrome c
release: Ca(2+) per se stimulated the release, whereas Ca(2+)-induced
depolarisation inhibited it. This dual effect caused a non-monotonous
dose-dependence of cytochrome c release on Ca(2+). In intact acinar cells,
cytochrome c release, caspase activation and apoptosis were all stimulated by ROS
and Ca(2+), 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 Ca(2+ )and ROS on acinar cell death. They
suggest that the extent of apoptosis in pancreatitis is regulated by the
interplay between ROS, Delta Psi m and Ca(2+). Stabilising mitochondria against
loss of Delta Psi m may represent a strategy to mitigate the severity of
pancreatitis.
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