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Original article
Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP
  1. Rajarshi Mukherjee1,2,
  2. Olga A Mareninova3,
  3. Irina V Odinokova3,4,
  4. Wei Huang1,2,5,
  5. John Murphy1,2,
  6. Michael Chvanov1,2,
  7. Muhammad A Javed1,2,
  8. Li Wen1,2,
  9. David M Booth1,2,
  10. Matthew C Cane2,
  11. Muhammad Awais1,2,
  12. Bruno Gavillet6,
  13. Rebecca M Pruss7,
  14. Sophie Schaller7,
  15. Jeffery D Molkentin8,
  16. Alexei V Tepikin1,2,
  17. Ole H Petersen9,
  18. Stephen J Pandol3,
  19. Ilya Gukovsky3,
  20. David N Criddle1,2,
  21. Anna S Gukovskaya3,
  22. Robert Sutton1,2
  23. and NIHR Pancreas Biomedical Research Unit1
    1. 1NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
    2. 2Institute of Translational Medicine, University of Liverpool, Liverpool, UK
    3. 3Veterans 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
    4. 4Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
    5. 5Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
    6. 6Debiopharm Research and Manufacturing S.A., Lausanne, Switzerland
    7. 7Trophos S.A., Marseille, France
    8. 8Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA
    9. 9Cardiff School of Biosciences, University of Cardiff, Cardiff, Wales, UK
    1. Correspondence to Professor Robert Sutton, NIHR Liverpool Pancreas Biomedical Research Unit, 5th Floor UCD, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK; r.sutton{at} Anna S. Gukovskaya, UCLA/Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles Veterans Affairs Healthcare Center, 11301 Wilshire Blvd., Blg. 258, Rm. 340, Los Angeles, California 90073, USA; agukovsk{at}


    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.


    This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:

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