RRC ID 36011
Author Mukherjee R, Mareninova OA, Odinokova IV, Huang W, Murphy J, Chvanov M, Javed MA, Wen L, Booth DM, Cane MC, Awais M, Gavillet B, Pruss RM, Schaller S, Molkentin JD, Tepikin AV, Petersen OH, Pandol SJ, Gukovsky I, Criddle DN, Gukovskaya AS, Sutton R, NIHR Pancreas Biomedical Research Unit.
Title Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP.
Journal Gut
Abstract 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.
Volume 65(8)
Pages 1333-46
Published 2016-8-1
DOI 10.1136/gutjnl-2014-308553
PII gutjnl-2014-308553
PMID 26071131
PMC PMC4920725
MeSH Acinar Cells* / drug effects Acinar Cells* / metabolism Acinar Cells* / pathology Animals Autophagy / drug effects Calcium / metabolism Cell Culture Techniques Disease Models, Animal Humans Inositol Phosphates / metabolism Inositol Phosphates / pharmacology Mice Mitochondria / enzymology Mitochondrial Membrane Transport Proteins* / antagonists & inhibitors Mitochondrial Membrane Transport Proteins* / metabolism Mitochondrial Permeability Transition Pore Mitochondrial Proteins / metabolism* Necrosis Pancreas* / drug effects Pancreas* / metabolism Pancreas* / pathology Pancreatitis, Acute Necrotizing* / chemically induced Pancreatitis, Acute Necrotizing* / metabolism Pancreatitis, Acute Necrotizing* / pathology Phosphoprotein Phosphatases / metabolism*
IF 19.819
Times Cited 62
Mice RBRC00806