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

Duman, MN; Angeloski, A; Johnson, MS; Rawling, T

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

Duman, MN Angeloski, A

Johnson, MS Rawling, T

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Publisher:: ROYAL SOC CHEMISTRY
Publication Type:: Journal Article
Citation:: Green Chemistry, 2023, 25, (15), pp. 6067-6076
Issue Date:: 2023-07-14

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Field	Value	Language
dc.contributor.author	Duman, MN
dc.contributor.author	Angeloski, A https://orcid.org/0000-0003-4395-1829
dc.contributor.author	Johnson, MS
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.date.accessioned	2024-02-06T03:06:59Z
dc.date.available	2024-02-06T03:06:59Z
dc.date.issued	2023-07-14
dc.identifier.citation	Green Chemistry, 2023, 25, (15), pp. 6067-6076
dc.identifier.issn	1463-9262
dc.identifier.issn	1463-9270
dc.identifier.uri	http://hdl.handle.net/10453/175353
dc.description.abstract	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.
dc.language	English
dc.publisher	ROYAL SOC CHEMISTRY
dc.relation.ispartof	Green Chemistry
dc.relation.isbasedon	10.1039/d3gc00151b
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject	03 Chemical Sciences
dc.subject.classification	Organic Chemistry
dc.subject.classification	34 Chemical sciences
dc.title	Aromatic long chain cations of amphiphilic ionic liquids permeabilise the inner mitochondrial membrane and induce mitochondrial dysfunction at cytotoxic concentrations
dc.type	Journal Article
utslib.citation.volume	25
utslib.for	03 Chemical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	open_access	*
utslib.copyright.embargo	2024-07-14T00:00:00+1000Z
dc.date.updated	2024-02-06T03:06:58Z
pubs.issue	15
pubs.publication-status	Published
pubs.volume	25
utslib.citation.issue	15

Abstract:

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.

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http://hdl.handle.net/10453/175353