Supramolecular zippers elicit interbilayer adhesion of membranes producing cell death



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Almendro Vedia, Víctor G. and García, Carolina and Ahijado Guzmán, Rubén and de la Fuente Herreruela, Diego and Muñoz Úbeda, Mónica and Natale, Paolo and Viñas, Montserrat H. and Albuquerque, Rodrigo Queiroz and Guerrero Martínez, Andrés and Monroy, Francisco and Lillo, M. Pilar and López-Montero, Iván (2018) Supramolecular zippers elicit interbilayer adhesion of membranes producing cell death. Biochimica et Biophysica Acta (BBA) - General Subjects, 1862 (12). pp. 2824-2834. ISSN 03044165

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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.

Item Type:Article
Additional Information:

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)

Uncontrolled Keywords:Fibroblasts; Mitochondria; Giant vesicles; H-aggregate; NAO
Subjects:Sciences > Chemistry > Chemistry, Physical and theoretical
Medical sciences > Biology > Molecular biology
ID Code:60119
Deposited On:22 Apr 2020 18:16
Last Modified:22 Apr 2020 18:16

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