A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechani...

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Autores principales:	Giulia di Punzio, Micol Gilberti, Enrico Baruffini, Tiziana Lodi, Claudia Donnini, Cristina Dallabona
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	yeast mitochondrial DNA depletion syndromes (MDS) drug repurposing MPV17 SYM1 POLG Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/c815fa1787db422e86f0be91e24775b9
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spelling	oai:doaj.org-article:c815fa1787db422e86f0be91e24775b92021-11-25T17:54:29ZA Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool10.3390/ijms2222122231422-00671661-6596https://doaj.org/article/c815fa1787db422e86f0be91e24775b92021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12223https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene <i>SYM1</i>. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.Giulia di PunzioMicol GilbertiEnrico BaruffiniTiziana LodiClaudia DonniniCristina DallabonaMDPI AGarticleyeastmitochondrial DNA depletion syndromes (MDS)drug repurposingMPV17SYM1POLGBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12223, p 12223 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	yeast mitochondrial DNA depletion syndromes (MDS) drug repurposing MPV17 SYM1 POLG Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	yeast mitochondrial DNA depletion syndromes (MDS) drug repurposing MPV17 SYM1 POLG Biology (General) QH301-705.5 Chemistry QD1-999 Giulia di Punzio Micol Gilberti Enrico Baruffini Tiziana Lodi Claudia Donnini Cristina Dallabona A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
description	Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene <i>SYM1</i>. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.
format	article
author	Giulia di Punzio Micol Gilberti Enrico Baruffini Tiziana Lodi Claudia Donnini Cristina Dallabona
author_facet	Giulia di Punzio Micol Gilberti Enrico Baruffini Tiziana Lodi Claudia Donnini Cristina Dallabona
author_sort	Giulia di Punzio
title	A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
title_short	A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
title_full	A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
title_fullStr	A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
title_full_unstemmed	A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
title_sort	yeast-based repurposing approach for the treatment of mitochondrial dna depletion syndromes led to the identification of molecules able to modulate the dntp pool
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c815fa1787db422e86f0be91e24775b9
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A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool

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