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Lookup NU author(s): Dr Tarek Mamdouh AbdelghanyORCiD, Lanyu Fan, Dr Satomi MiwaORCiD, Dr Agnieszka Bronowska
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The AuthorsMethylimidazolium ionic liquids (MILs) are solvents used in an increasing variety of industrial applications. Recent studies identified the 8C MIL (M8OI) contaminating the environment, detected exposure in humans and proposed M8OI to be a potential trigger for the autoimmune liver disease primary biliary cholangitis (PBC). To gain a better understanding of any PBC trigger mechanism(s), the interaction of M8OI with mitochondria has been examined. M8OI inhibited oxygen consumption in intact cells and induced cell death (IC50%–10 μM). Results from permeabilized cells indicated M8OI inhibits the mitochondrial electron transport chain at complex I, not complexes II, III or IV. Accordingly, succinate supported mitochondrial oxygen consumption and reduced cell death in the presence of M8OI. M8OI inhibited NADH oxidation by both mitochondrial membranes and purified complex I with IC50% values of 470 μM and 340 μM respectively. Based on direct determinations of M8OI in non-mitochondrial and mitochondrial compartments, toxic M8OI concentrations were estimated to result in mitochondrial concentrations commensurate with complex I inhibition. Mitochondrial accumulation followed by complex I inhibition is therefore a possible molecular initiating event for M8OI-dependent cell death. NADH oxidation by purified complex I in combination with a flavin-site electron acceptor was not inhibited by M8OI, indicating no interaction of M8OI at the NADH-binding active site. Modelling supported M8OI binding to the ubiquinone-binding site. By inhibiting turnover, M8OI also gave rise to increases in complex-I-linked reactive oxygen species. However, inhibitors of oxidative stress did not affect M8OI-mediated cell death. The metabolic consequences of M8OI-mediated complex I inhibition, not increased reactive oxygen species production, are therefore the likely cause of apoptotic cell death. Understanding the effects on complex I and the pathways activated and leading to cell death may be informative regarding mitochondrial stress, cell death and diseases such as PBC.
Author(s): Abdelghany TM, Bosak J, Leitch AC, Charlton A, Fan L, Aljehani FA, Alkhathami OH, Hedya SA, Miwa S, Bronowska AK, Hirst J, Wright MC
Publication type: Article
Publication status: Published
Journal: Chemosphere
Year: 2025
Volume: 374
Print publication date: 01/04/2025
Online publication date: 18/02/2025
Acceptance date: 09/02/2025
Date deposited: 03/03/2025
ISSN (print): 0045-6535
ISSN (electronic): 1879-1298
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/j.chemosphere.2025.144213
DOI: 10.1016/j.chemosphere.2025.144213
Data Access Statement: Data will be made available on request.
