title: Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Mareninova
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Odinokova
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: John
authors.initials: J
authors.lastname: Murphy
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Chvanov
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Javed
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Booth
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cane
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Awais
authors.affiliation: Debiopharm Research and Manufacturing S.A., Lausanne, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gavillet
authors.affiliation: Trophos S.A., Marseille, France.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
authors.affiliation: Trophos S.A., Marseille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Schaller
authors.affiliation: Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tepikin
authors.affiliation: Cardiff School of Biosciences, University of Cardiff, Cardiff, Wales, UK.
authors.forename: Ole H
authors.initials: OH
authors.lastname: Petersen
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Robert
authors.identifier: 0000-0001-6600-562X
authors.initials: R
authors.lastname: Sutton
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009336:Necrosis; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*
chemical_list: D007295:Inositol Phosphates; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; C516441:inositol trispyrophosphate; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases; D002118:Calcium
keywords: ACUTE PANCREATITIS; CELL DEATH; CELL SIGNALLING