1. Volume 144, Issue 2, Pages 265-269 (February 2013)
Preventing Pancreatitis by Protecting the Mitochondrial Permeability Transition Pore 
Markus M. Lerch 
Gastroenterology 
Volume 144, Issue 2, Pages (February 2013)
DOI: /j.gastro
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2. Figure 1
Cholecystokinin (CCK) and ethanol cooperate at the mitochondrial permeability transition pore (MPTP) in sensitizing the pancreatic acinar cell towards injury. CCK, via the CCK receptor (CCKR), releases cyclic ADP-ribose, nicotinic acid adenine dinucleotide phosphate, and inostitol triphosphate (IP3), all of which can induce Ca++ to be released into the cytosol from stores, either as physiologic Ca++ oscillations or as cytotoxic Ca++ waves. When the MPTP is overwhelmed by a Ca++ wave, this leads to permanent (rather than transient) MPTP opening with the consequence of a collapse of the mitochondrial membrane potential, ΔΨm, causing permeabilization of the outer mitochondrial membrane, followed by acinar cell necrosis, as well as apoptosis via leakage of cytochrome C into the cytosol. Ethanol is metabolized to either fatty acid ethyl ester (FAEE), which contributes to Ca++ release via IP3, or undergoes oxidative catalysis by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase 2 (ALDH2). The latter is mitochondrially localized and competes for NAD+ with the MPTP. In concert, physiologic CCK concentrations together with ethanol can thus convert a transient opening of the MPTP into a permanent one, leading to acinar cell damage. Deletion of cyclophillin D, a major component of the MPTP prevents both, the CCK and the ethanol effect on the MPTP and prevents acinar cell necrosis. Blue arrows indicate effects of 1 component on the other.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2013 AGA Institute Terms and Conditions