RT Journal Article
T1 Supramolecular zippers elicit interbilayer adhesion of membranes producing cell death
A1 Almendro Vedia, Víctor Galileo
A1 García, Carolina
A1 Ahijado Guzmán, Rubén
A1 de la Fuente Herreruela, Diego
A1 Muñoz Úbeda, Mónica
A1 Natale, Paolo
A1 Viñas, Montserrat H.
A1 Albuquerque, Rodrigo Queiroz
A1 Guerrero Martínez, Andrés
A1 Monroy, Francisco
A1 Lillo, M. Pilar
A1 López-Montero, Iván
AB Background: The fluorescent dye 10-N-nonyl acridine orange (NAO) is widely used as a mitochondrial marker. NAO was reported to have cytotoxic effects in cultured eukaryotic cells when incubated at high concentrations. Although the biochemical response of NAO-induced toxicity has been well identified, the underlying molecular mechanism has not yet been explored in detail. Methods: We use optical techniques, including fluorescence confocal microscopy and lifetime imaging microscopy (FLIM) both in model membranes built up as giant unilamellar vesicles (GUVs) and cultured cells. These experiments are complemented with computational studies to unravel the molecular mechanism that makes NAO cytotoxic. Results: We have obtained direct evidence that NAO promotes strong membrane adhesion of negatively charged vesicles. The attractive forces are derived from van der Waals interactions between anti-parallel H-dimers of NAO molecules from opposing bilayers. Semi-empirical calculations have confirmed the supramolecular scenario by which anti-parallel NAO molecules form a zipper of bonds at the contact region. The membrane remodeling effect of NAO, as well as the formation of H-dimers, was also confirmed in cultured fibroblasts, as shown by the ultrastructure alteration of the mitochondrial cristae. Conclusions: We conclude that membrane adhesion induced by NAO stacking accounts for the supramolecular basis of its cytotoxicity. General significance: Mitochondria are a potential target for cancer and gene therapies. The alteration of the mitochondrial structure by membrane remodeling agents able to form supramolecular assemblies via adhesion properties could be envisaged as a new therapeutic strategy.
PB Elsevier
SN 03044165
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/12296
UL https://hdl.handle.net/20.500.14352/12296
LA eng
NO The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (ERC grant agreement n° 338133)
NO Unión Europea. FP7
NO Unión Europea. Horizonte 2020
NO Ministerio de Economía y Competitividad (MINECO)
NO Comunidad de Madrid
DS Docta Complutense
RD 7 oct 2024