Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP.
机构：[1]NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.[2]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.[3]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.[4]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.四川大学华西医院[5]Institute of Translational Medicine, University of Liverpool, Liverpool, UK.[6]Debiopharm Research and Manufacturing S.A., Lausanne, Switzerland.[7]Trophos S.A., Marseille, France.[8]Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA.[9]Cardiff School of Biosciences, University of Cardiff, Cardiff, Wales, UK.
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.
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基金：
This work was supported by US Veterans Administration Merit Review
(ASG), NIH grants R01DK59936 (ASG) and R01AA19730 (IG and OAM), Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (SJP and ASG),
American Gastroenterological Association Foundation Designated Research Scholar
Award in Pancreatitis (OAM), Russian Federation BR grant 09-04-00739 (IVO), UK/
China Postgraduate Research Scholarship for Excellence (WH), Liverpool China
Scholarship Council Award (LW), CORE, UK (RM, JM, MAJ), UK Medical Research
Council (DMB, MC, MCC, OHP, AVT, DNC and RS), Royal College of Surgeons of
England (MAJ) and UK NIHR Biomedical Research Unit Funding Scheme (MA, AVT,
DNC and RS).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类|1 区医学
小类|1 区胃肠肝病学
最新[2023]版：
大类|1 区医学
小类|1 区胃肠肝病学
第一作者：
第一作者机构：[1]NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
通讯作者：
通讯机构：[1]NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Liverpool, UK.[2]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.[*1]NIHR Liverpool Pancreas Biomedical Research Unit, 5th Floor UCD, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK[*2]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
推荐引用方式(GB/T 7714)：
Mukherjee Rajarshi,Mareninova Olga A,Odinokova Irina V,et al.Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP.[J].Gut.2016,65(8):1333-46.doi:10.1136/gutjnl-2014-308553.
APA：
Mukherjee Rajarshi,Mareninova Olga A,Odinokova Irina V,Huang Wei,Murphy John...&Sutton Robert.(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)
MLA：
Mukherjee Rajarshi,et al."Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP.".Gut 65..8(2016):1333-46
医学