RT Journal Article
SR Electronic
T1 Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1333
OP 1346
DO 10.1136/gutjnl-2014-308553
VO 65
IS 8
A1 Rajarshi Mukherjee
A1 Olga A Mareninova
A1 Irina V Odinokova
A1 Wei Huang
A1 John Murphy
A1 Michael Chvanov
A1 Muhammad A Javed
A1 Li Wen
A1 David M Booth
A1 Matthew C Cane
A1 Muhammad Awais
A1 Bruno Gavillet
A1 Rebecca M Pruss
A1 Sophie Schaller
A1 Jeffery D Molkentin
A1 Alexei V Tepikin
A1 Ole H Petersen
A1 Stephen J Pandol
A1 Ilya Gukovsky
A1 David N Criddle
A1 Anna S Gukovskaya
A1 Robert Sutton
YR 2016
UL http://gut.bmj.com/content/65/8/1333.abstract
AB Objective Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established.Design We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis.Results MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished.Conclusions This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease.