Abstract
A polymorphism in the ATP synthase 8 (ATP8) gene of the murine mitochondrial genome, G-to-T transversion at position 7778, has been suggested to increase susceptibility to multiple autoimmune diseases, including autoimmune pancreatitis (AIP). The polymorphism also induces mitochondrial reactive oxygen species generation, secretory dysfunction and β-cell mass adaptation. Here, we have used two conplastic mouse strains, C57BL/6N-mtAKR/J (B6-mtAKR; nt7778 G; control) and C57BL/6N-mtFVB/N (B6-mtFVB; nt7778 T), to address the question if the polymorphism also affects the course of cerulein-induced acute pancreatitis in mice. Therefore, two age groups of mice (3 and 12-month-old, respectively) were subjected to up to 7 injections of the secretagogue cerulein (50 µg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of α-amylase and activities of myeloperoxidase (MPO) in lung tissue. A comparison of cerulein-induced pancreatic tissue damage and increases of α-amylase and MPO activities showed no differences between the age-matched groups of both strains. Interestingly, histological evaluation of pancreatic tissue of both untreated and cerulein-treated B6-mtAKR and B6-mtFVB mice also revealed the presence of infiltrates of immune cells surrounding ducts and vessels; a finding that is compatible with an early stage of AIP. After recovery from cerulein-induced pancreatitis (day 7 after the injections), 12-month-old B6-mtFVB mice but not B6-mtAKR mice displayed aggravated lymphocytic lesions. A comparison of 12-month-old mice with other age groups of both strains revealed that lymphocytic foci were largely absent in 3-month-old mice, while 24-month-old mice were more affected. Together, our data suggest that the mtDNA nt7778 G/T polymorphism does not aggravate cerulein-induced acute pancreatitis. Autoimmune-like lesions, however, may progress faster if additional tissue damage occurs.
Highlights
A growing body of evidence suggests that mitochondrial dysfunctions are crucially involved in the development of acute pancreatitis (AP) [1], a potentially deadly disease that is among the leading causes of hospitalization for gastrointestinal disorders worldwide [2,3]
With respect to the mitochondrial Atp8 gene, the nucleotide transition nt8406 C/T has been shown to be associated with multiple sclerosis [34], whereas the mutation nt8529 G/A results in a defective mitochondrial oxidative phosphorylation with cardiomyopathy and neuropathy [35]
We have addressed the question if the murine mitochondrial DNA (mtDNA) polymorphism nt7778 G/T affects the susceptibility to develop severe AP upon challenge with the standard trigger cerulein
Summary
A growing body of evidence suggests that mitochondrial dysfunctions are crucially involved in the development of acute pancreatitis (AP) [1], a potentially deadly disease that is among the leading causes of hospitalization for gastrointestinal disorders worldwide [2,3]. Mitochondrial DNA (mtDNA) variations have been identified that cause maternally inherited mtDNA disorders or lead to functional changes which predispose individuals for severe diseases [16,17]. A systematic analysis of mtDNA variations, is hampered by the fact that targeted mutation of the mitochondrial genome currently remains technically difficult due to lack of recombination and the possibility of heteroplasmy. This is one of the reasons why data on PLOS ONE | www.plosone.org mtDNA nt7778 G/T Polymorphism Augments Formation of Lymphocytic Foci the role of mitochondrial DNA polymorphisms in the pathogenesis of pancreatitis are still very rare
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