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Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP

Mukherjee, R., Mareninova, O. A., Odinokova, I. V., Huang, W., Murphy, J., Chvanov, M., Javed, M. A., Wen, L., Booth, D. M., Cane, M. C., Awais, M., Gavillet, B., Pruss, R. M., Schaller, S., Molkentin, J. D., Tepikin, A. V., Petersen, Ole Holger, Pandol, S. J., Gukovsky, I., Criddle, D. N., Gukovskaya, A. S., Sutton, R., Latawiec, D., Rajamanoharan, D., Mclaughlin, E., Ghaneh, P., Halloran, C., Neoptolemos, J. P., Raraty, M. G. and French, S. W. 2016. Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut 65 (8) , pp. 1333-1346. 10.1136/gutjnl-2014-308553

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology
Additional Information: 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: http://creativecommons.org/licenses/by/4.0/
Publisher: BMJ Publishing Group Ltd
ISSN: 0017-5749
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 7 April 2015
Last Modified: 04 Jun 2017 08:12
URI: http://orca.cf.ac.uk/id/eprint/74278

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