Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization

Phenoxazine derivatives such as Nile Blue analogues are assumed to be increasingly relevant in cell biology due to their fluorescence staining capabilities and antifungal and anticancer activities. However, the mechanisms underlying their effects remain poorly elucidated. Using <i>S. cerevisia...

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Autores principales:	João Carlos Canossa Ferreira, Carla Lopes, Ana Preto, Maria Sameiro Torres Gonçalves, Maria João Sousa
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	benzo[<i>a</i>]phenoxazine derivative Nile Blue analogue cell death mechanism vacuole/lysosome membrane permeabilization yeast as a eukaryotic cell model Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/cd6855bf281f4521b269b001ba9139d2
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spelling	oai:doaj.org-article:cd6855bf281f4521b269b001ba9139d22021-11-25T18:06:18ZNovel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization10.3390/jof71109712309-608Xhttps://doaj.org/article/cd6855bf281f4521b269b001ba9139d22021-11-01T00:00:00Zhttps://www.mdpi.com/2309-608X/7/11/971https://doaj.org/toc/2309-608XPhenoxazine derivatives such as Nile Blue analogues are assumed to be increasingly relevant in cell biology due to their fluorescence staining capabilities and antifungal and anticancer activities. However, the mechanisms underlying their effects remain poorly elucidated. Using <i>S. cerevisiae</i> as a eukaryotic model, we found that BaP1, a novel 5- and 9-<i>N</i>-substituted benzo[<i>a</i>]phenoxazine synthesized in our laboratory, when used in low concentrations, accumulates and stains the vacuolar membrane and the endoplasmic reticulum. In contrast, at higher concentrations, BaP1 stains lipid droplets and induces a regulated cell death process mediated by vacuolar membrane permeabilization. BaP1 also induced mitochondrial fragmentation and depolarization but did not lead to ROS accumulation, changes in intracellular Ca<sup>2+</sup>, or loss of plasma membrane integrity. Additionally, our results show that the cell death process is dependent on the vacuolar protease Pep4p and that the vacuole permeabilization results in its translocation from the vacuole to the cytosol. In addition, although nucleic acids are commonly described as targets of benzo[<i>a</i>]phenoxazines, we did not find any alterations at the DNA level. Our observations highlight BaP1 as a promising molecule for pharmacological application, using vacuole membrane permeabilization as a targeted approach.João Carlos Canossa FerreiraCarla LopesAna PretoMaria Sameiro Torres GonçalvesMaria João SousaMDPI AGarticlebenzo[<i>a</i>]phenoxazine derivativeNile Blue analoguecell death mechanismvacuole/lysosome membrane permeabilizationyeast as a eukaryotic cell modelBiology (General)QH301-705.5ENJournal of Fungi, Vol 7, Iss 971, p 971 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	benzo[<i>a</i>]phenoxazine derivative Nile Blue analogue cell death mechanism vacuole/lysosome membrane permeabilization yeast as a eukaryotic cell model Biology (General) QH301-705.5
spellingShingle	benzo[<i>a</i>]phenoxazine derivative Nile Blue analogue cell death mechanism vacuole/lysosome membrane permeabilization yeast as a eukaryotic cell model Biology (General) QH301-705.5 João Carlos Canossa Ferreira Carla Lopes Ana Preto Maria Sameiro Torres Gonçalves Maria João Sousa Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization
description	Phenoxazine derivatives such as Nile Blue analogues are assumed to be increasingly relevant in cell biology due to their fluorescence staining capabilities and antifungal and anticancer activities. However, the mechanisms underlying their effects remain poorly elucidated. Using <i>S. cerevisiae</i> as a eukaryotic model, we found that BaP1, a novel 5- and 9-<i>N</i>-substituted benzo[<i>a</i>]phenoxazine synthesized in our laboratory, when used in low concentrations, accumulates and stains the vacuolar membrane and the endoplasmic reticulum. In contrast, at higher concentrations, BaP1 stains lipid droplets and induces a regulated cell death process mediated by vacuolar membrane permeabilization. BaP1 also induced mitochondrial fragmentation and depolarization but did not lead to ROS accumulation, changes in intracellular Ca<sup>2+</sup>, or loss of plasma membrane integrity. Additionally, our results show that the cell death process is dependent on the vacuolar protease Pep4p and that the vacuole permeabilization results in its translocation from the vacuole to the cytosol. In addition, although nucleic acids are commonly described as targets of benzo[<i>a</i>]phenoxazines, we did not find any alterations at the DNA level. Our observations highlight BaP1 as a promising molecule for pharmacological application, using vacuole membrane permeabilization as a targeted approach.
format	article
author	João Carlos Canossa Ferreira Carla Lopes Ana Preto Maria Sameiro Torres Gonçalves Maria João Sousa
author_facet	João Carlos Canossa Ferreira Carla Lopes Ana Preto Maria Sameiro Torres Gonçalves Maria João Sousa
author_sort	João Carlos Canossa Ferreira
title	Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization
title_short	Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization
title_full	Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization
title_fullStr	Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization
title_full_unstemmed	Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization
title_sort	novel nile blue analogue stains yeast vacuolar membrane, endoplasmic reticulum, and lipid droplets, inducing cell death through vacuole membrane permeabilization
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cd6855bf281f4521b269b001ba9139d2
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Novel Nile Blue Analogue Stains Yeast Vacuolar Membrane, Endoplasmic Reticulum, and Lipid Droplets, Inducing Cell Death through Vacuole Membrane Permeabilization

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