Mitochondrial Targeting of Antioxidants Alters Pancreatic Acinar Cell Bioenergetics and Determines Cell Fate

Armstrong, Jane A, Cash, Nicole J, Morton, Jack C, Tepikin, Alexei V, Sutton, Robert ORCID: 0000-0001-6600-562X and Criddle, DN ORCID: 0000-0003-2952-8450 (2019) Mitochondrial Targeting of Antioxidants Alters Pancreatic Acinar Cell Bioenergetics and Determines Cell Fate. International Journal of Molecular Sciences, 20 (7). E1700-.

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Official URL: http://mdpi.com/1422-0067/20/7/1700

Abstract

Mitochondrial dysfunction is a core feature of acute pancreatitis, a severe disease in which oxidative stress is elevated. Mitochondrial targeting of antioxidants is a potential therapeutic strategy for this and other diseases, although thus far mixed results have been reported. We investigated the effects of mitochondrial targeting with the antioxidant MitoQ on pancreatic acinar cell bioenergetics, adenosine triphosphate (ATP) production and cell fate, in comparison with the non-antioxidant control decyltriphenylphosphonium bromide (DecylTPP) and general antioxidant N-acetylcysteine (NAC). MitoQ (µM range) and NAC (mM range) caused sustained elevations of basal respiration and the inhibition of spare respiratory capacity, which was attributable to an antioxidant action since these effects were minimal with DecylTPP. Although MitoQ but not DecylTPP decreased cellular NADH levels, mitochondrial ATP turnover capacity and cellular ATP concentrations were markedly reduced by both MitoQ and DecylTPP, indicating a non-specific effect of mitochondrial targeting. All three compounds were associated with a compensatory elevation of glycolysis and concentration-dependent increases in acinar cell apoptosis and necrosis. These data suggest that reactive oxygen species (ROS) contribute a significant negative feedback control of basal cellular metabolism. Mitochondrial targeting using positively charged molecules that insert into the inner mitochondrial member appears to be deleterious in pancreatic acinar cells, as does an antioxidant strategy for the treatment of acute pancreatitis.

Item Type:	Article
Uncontrolled Keywords:	oxidative stress, mitochondrial dysfunction, MitoQ, DecylTPP, Seahorse, pancreatic acinar cell, antioxidants, mitochondrial targeting
Depositing User:	Symplectic Admin
Date Deposited:	09 Apr 2019 10:39
Last Modified:	19 Jan 2023 00:54
DOI:	10.3390/ijms20071700
Open Access URL:	https://doi.org/10.3390/ijms20071700
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3036257