Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species

ABSTRACT MGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria. In this study, we identified MGE1 as a multicopy suppressor of susceptibility to the antifungal fluconazole in the model yeast Saccharomyces cerevisiae. We demonstrate that this phen...

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Autores principales:	Liesbeth Demuyser, Erwin Swinnen, Alessandro Fiori, Beatriz Herrera-Malaver, Kevin Verstrepen, Patrick Van Dijck
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Candida albicans Candida glabrata Fe-S cluster Mge1 Saccharomyces cerevisiae antifungal susceptibility Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8a476b28121e442d88e9040a8950790a
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spelling	oai:doaj.org-article:8a476b28121e442d88e9040a8950790a2021-11-15T15:51:44ZMitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species10.1128/mBio.00201-172150-7511https://doaj.org/article/8a476b28121e442d88e9040a8950790a2017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00201-17https://doaj.org/toc/2150-7511ABSTRACT MGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria. In this study, we identified MGE1 as a multicopy suppressor of susceptibility to the antifungal fluconazole in the model yeast Saccharomyces cerevisiae. We demonstrate that this phenomenon is not exclusively dependent on the integrity of the mitochondrial DNA or on the presence of the drug efflux pump Pdr5. Instead, we show that the increased dosage of Mge1 plays a protective role by retaining increased amounts of ergosterol upon fluconazole treatment. Iron metabolism and, more particularly, Fe-S cluster formation are involved in regulating this process, since the responsible Hsp70 chaperone, Ssq1, is required. Additionally, we show the necessity but, by itself, insufficiency of activating the iron regulon in establishing the Mge1-related effect on drug susceptibility. Finally, we confirm a similar role for Mge1 in fluconazole susceptibility in the pathogenic fungi Candida glabrata and Candida albicans. IMPORTANCE Although they are mostly neglected compared to bacterial infections, fungal infections pose a serious threat to the human population. While some of them remain relatively harmless, infections that reach the bloodstream often become lethal. Only a few therapies are available, and resistance of the pathogen to these drugs is a frequently encountered problem. It is thus essential that more research is performed on how these pathogens cope with the treatment and cause recurrent infections. Baker’s yeast is often used as a model to study pathogenic fungi. We show here, by using this model, that iron metabolism and the formation of the important iron-sulfur clusters are involved in regulating susceptibility to fluconazole, the most commonly used antifungal drug. We show that the same process likely also occurs in two of the most regularly isolated pathogenic fungi, Candida glabrata and Candida albicans.Liesbeth DemuyserErwin SwinnenAlessandro FioriBeatriz Herrera-MalaverKevin VerstrepenPatrick Van DijckAmerican Society for MicrobiologyarticleCandida albicansCandida glabrataFe-S clusterMge1Saccharomyces cerevisiaeantifungal susceptibilityMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans Candida glabrata Fe-S cluster Mge1 Saccharomyces cerevisiae antifungal susceptibility Microbiology QR1-502
spellingShingle	Candida albicans Candida glabrata Fe-S cluster Mge1 Saccharomyces cerevisiae antifungal susceptibility Microbiology QR1-502 Liesbeth Demuyser Erwin Swinnen Alessandro Fiori Beatriz Herrera-Malaver Kevin Verstrepen Patrick Van Dijck Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species
description	ABSTRACT MGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria. In this study, we identified MGE1 as a multicopy suppressor of susceptibility to the antifungal fluconazole in the model yeast Saccharomyces cerevisiae. We demonstrate that this phenomenon is not exclusively dependent on the integrity of the mitochondrial DNA or on the presence of the drug efflux pump Pdr5. Instead, we show that the increased dosage of Mge1 plays a protective role by retaining increased amounts of ergosterol upon fluconazole treatment. Iron metabolism and, more particularly, Fe-S cluster formation are involved in regulating this process, since the responsible Hsp70 chaperone, Ssq1, is required. Additionally, we show the necessity but, by itself, insufficiency of activating the iron regulon in establishing the Mge1-related effect on drug susceptibility. Finally, we confirm a similar role for Mge1 in fluconazole susceptibility in the pathogenic fungi Candida glabrata and Candida albicans. IMPORTANCE Although they are mostly neglected compared to bacterial infections, fungal infections pose a serious threat to the human population. While some of them remain relatively harmless, infections that reach the bloodstream often become lethal. Only a few therapies are available, and resistance of the pathogen to these drugs is a frequently encountered problem. It is thus essential that more research is performed on how these pathogens cope with the treatment and cause recurrent infections. Baker’s yeast is often used as a model to study pathogenic fungi. We show here, by using this model, that iron metabolism and the formation of the important iron-sulfur clusters are involved in regulating susceptibility to fluconazole, the most commonly used antifungal drug. We show that the same process likely also occurs in two of the most regularly isolated pathogenic fungi, Candida glabrata and Candida albicans.
format	article
author	Liesbeth Demuyser Erwin Swinnen Alessandro Fiori Beatriz Herrera-Malaver Kevin Verstrepen Patrick Van Dijck
author_facet	Liesbeth Demuyser Erwin Swinnen Alessandro Fiori Beatriz Herrera-Malaver Kevin Verstrepen Patrick Van Dijck
author_sort	Liesbeth Demuyser
title	Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species
title_short	Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species
title_full	Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species
title_fullStr	Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species
title_full_unstemmed	Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species
title_sort	mitochondrial cochaperone mge1 is involved in regulating susceptibility to fluconazole in <italic toggle="yes">saccharomyces cerevisiae</italic> and <italic toggle="yes">candida</italic> species
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/8a476b28121e442d88e9040a8950790a
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Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in <italic toggle="yes">Saccharomyces cerevisiae</italic> and <italic toggle="yes">Candida</italic> Species

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