Aromatic long chain cations of amphiphilic ionic liquids permeabilise the inner mitochondrial membrane and induce mitochondrial dysfunction at cytotoxic concentrations

• Published in: Green chemistry : an international journal and green chemistry resource : GC Vol. 25; no. 15; pp. 667 - 676
• Main Authors: Duman, Meryem-Nur, Angeloski, Alexander, Johnson, Michael S, Rawling, Tristan
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 31.07.2023
• Subjects: Anticancer properties; Antitumor agents; Cations; Cell membranes; Cytotoxicity; Disruption; Fluorescence; Fluorescence microscopy; Green chemistry; Industrial applications; Ionic liquids; Ions; Lipid bilayers; Lipids; Lipophilic; Lipophilicity; Membrane potential; Membranes; Mitochondria; Oxidative phosphorylation; Phosphorylation; Toxicity
• ISSN: 1463-9262; 1463-9270
• DOI: 10.1039/d3gc00151b

Understanding the cellular mechanisms by which amphiphilic ionic liquids (AmILs) induce cytotoxicity is an important step in the development of task-specific AmILs for safe industrial applications or as cytotoxic anticancer agents. Accumulated evidence suggests that AmILs kill cells by disrupting cellular membranes and/or inducing mitochondrial dysfunction. The cation of AmILs is lipophilic due to alkyl substitution, and lipophilic cations are a group of compounds known to accumulate in mitochondria in response to the membrane potential across the inner mitochondrial membrane (IMM). We therefore hypothesised that AmILs exert their cytotoxic effects by disrupting the IMM, the integrity of which is critical to several important cellular processes. Using fluorescence microscopy we show that a quinolinium-based AmIL rapidly accumulates in the mitochondria of HeLa cells. In a panel of AmILs we found that cytotoxicity correlates with their capacity to disrupt lipid bilayers, and that AmILs produce a range of cellular effects consistent with permeabilisation of the IMM at cytotoxic concentrations. Thus, AmILs depolarise the IMM, inhibit oxidative phosphorylation and ATP synthesis, and induce ROS formation. These effects were only induced by AmILs with aromatic cations substituted with long (decyl) alkyl chains, as these features promote accumulation in, and permeabilisation of, the IMM. These mechanistic insights help explain the structure-activity relationship governing AmILs cytotoxicity and may be used to rationally design either safe or cytotoxic AmILs. Aromatic long chain cations of amphiphilic ionic liquids (AmILs) accumulate in and permeabilise the IMM at their cytotoxic concentrations. The AmILs depolarise IMM, inhibit oxidative phosphorylation and ATP synthesis, and induce ROS formation.