The Role of EXD2 in the maintenance of mithocondrial homeostasis

Mitochondrial dysfunction arising from aberrant mitochondrial nucleic acid homeostasis has been associated with various pathologies. In this thesis, we aim to characterize a putative mitochondrial exonuclease, EXD2, and the consequences of its loss in cell metabolism. For that purpose we use three a...

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Detalhes bibliográficos
Autor: Aivio, Suvi Marjaana
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2014
País:España
Recursos:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/328716
Acesso em linha:http://hdl.handle.net/10803/328716
Access Level:acceso abierto
Palavra-chave:EXD2
WRN
HIF-1α
exonuclease
exoribonuclease
DNA
RNA
tRNA
sRNA
mithocondria
metabolism
aging
DNA repair
mithocondrial replication
breast cancer
hypoxia
Exonucleasa
Exoribonucleasa
Mitocondria
Metabolismo
Envejecimiento
Reparación del ADN
Replicación mitocondrial
Cancer de mama
Hipoxia
577
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repository_id_str
spelling The Role of EXD2 in the maintenance of mithocondrial homeostasisAivio, Suvi MarjaanaEXD2WRNHIF-1αexonucleaseexoribonucleaseDNARNAtRNAsRNAmithocondriametabolismagingDNA repairmithocondrial replicationbreast cancerhypoxiaExonucleasaExoribonucleasaMitocondriaMetabolismoEnvejecimientoReparación del ADNReplicación mitocondrialCancer de mamaHipoxia577Mitochondrial dysfunction arising from aberrant mitochondrial nucleic acid homeostasis has been associated with various pathologies. In this thesis, we aim to characterize a putative mitochondrial exonuclease, EXD2, and the consequences of its loss in cell metabolism. For that purpose we use three approaches: 1) Biochemical assays with bacterially purified EXD2 to study its enzymatic activity, 2) In vitro experiments with cell lines to study the phenotype of cells with altered EXD2-levels, and, 3) In vivo experiments with a mouse xenograft model and D.melanogaster to study the consequences of EXD2-loss in tumors and at the organismal level. Our work shows, that EXD2 is a uniquely versatile mammalian exonuclease able to bind and degrade various DNA and RNA substrates. We demonstrate that loss of EXD2 in cancer cells leads to alterations in mtDNA, various metabolic changes and aberrant hypoxia signaling. We also describe how, in vivo, this leads to inhibition of breast tumor growth and increased lifespan in fruitflies. Taken together, our observations provide a link between mitochondrial nucleic acid maintenance and large-scale metabolic alterations influencing tumor growth and aging.La disfunción mitocondrial que surge de la homeostasis de ácido nucleico mitocondrial aberrante se ha asociado con varias patologías. En esta tesis, se pretende caracterizar una exonucleasa putativo mitocondrial, EXD2, y las consecuencias de su pérdida en el metabolismo celular. Para ello utilizamos tres enfoques: 1) ensayos bioquímicos con EXD2 purificado de bacterias para estudiar su actividad enzimática, 2) los experimentos in vitro con líneas celulares para estudiar el fenotipo de las células con niveles de EXD2 alterados, y, 3) experimentos in vivo con modelo de xenotrasplante de ratón y D.melanogaster para estudiar las consecuencias de perdida de EXD2 en los tumores y en el nivel del organismo. Nuestro trabajo muestra que EXD2 es una exonucleasa mamíferos excepcionalmente versátil capaz de unirse y degradar diversos sustratos de ADN y ARN. Se demuestra que la pérdida de EXD2 en las células del cáncer conduce a alteraciones en el ADN mitocondrial, diversas alteraciones metabólicas y de señalización hipoxia aberrante. También describimos cómo, in vivo, esto conduce a la inhibición del crecimiento del tumor de mama y aumento de la vida útil en moscas de la fruta. En conjunto, nuestras observaciones proporcionan un enlace entre el mantenimiento de ácidos nucleicos mitocondriales y de gran escala alteraciones metabólicas que influyen en el crecimiento del tumor y el envejecimiento.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraStracker, TravisUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut201520162014info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion218 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/328716TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc/3.0/es/http://creativecommons.org/licenses/by-nc/3.0/es/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/3287162026-06-14T12:46:07Z
dc.title.none.fl_str_mv The Role of EXD2 in the maintenance of mithocondrial homeostasis
title The Role of EXD2 in the maintenance of mithocondrial homeostasis
spellingShingle The Role of EXD2 in the maintenance of mithocondrial homeostasis
Aivio, Suvi Marjaana
EXD2
WRN
HIF-1α
exonuclease
exoribonuclease
DNA
RNA
tRNA
sRNA
mithocondria
metabolism
aging
DNA repair
mithocondrial replication
breast cancer
hypoxia
Exonucleasa
Exoribonucleasa
Mitocondria
Metabolismo
Envejecimiento
Reparación del ADN
Replicación mitocondrial
Cancer de mama
Hipoxia
577
title_short The Role of EXD2 in the maintenance of mithocondrial homeostasis
title_full The Role of EXD2 in the maintenance of mithocondrial homeostasis
title_fullStr The Role of EXD2 in the maintenance of mithocondrial homeostasis
title_full_unstemmed The Role of EXD2 in the maintenance of mithocondrial homeostasis
title_sort The Role of EXD2 in the maintenance of mithocondrial homeostasis
dc.creator.none.fl_str_mv Aivio, Suvi Marjaana
author Aivio, Suvi Marjaana
author_facet Aivio, Suvi Marjaana
author_role author
dc.contributor.none.fl_str_mv Stracker, Travis
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv EXD2
WRN
HIF-1α
exonuclease
exoribonuclease
DNA
RNA
tRNA
sRNA
mithocondria
metabolism
aging
DNA repair
mithocondrial replication
breast cancer
hypoxia
Exonucleasa
Exoribonucleasa
Mitocondria
Metabolismo
Envejecimiento
Reparación del ADN
Replicación mitocondrial
Cancer de mama
Hipoxia
577
topic EXD2
WRN
HIF-1α
exonuclease
exoribonuclease
DNA
RNA
tRNA
sRNA
mithocondria
metabolism
aging
DNA repair
mithocondrial replication
breast cancer
hypoxia
Exonucleasa
Exoribonucleasa
Mitocondria
Metabolismo
Envejecimiento
Reparación del ADN
Replicación mitocondrial
Cancer de mama
Hipoxia
577
description Mitochondrial dysfunction arising from aberrant mitochondrial nucleic acid homeostasis has been associated with various pathologies. In this thesis, we aim to characterize a putative mitochondrial exonuclease, EXD2, and the consequences of its loss in cell metabolism. For that purpose we use three approaches: 1) Biochemical assays with bacterially purified EXD2 to study its enzymatic activity, 2) In vitro experiments with cell lines to study the phenotype of cells with altered EXD2-levels, and, 3) In vivo experiments with a mouse xenograft model and D.melanogaster to study the consequences of EXD2-loss in tumors and at the organismal level. Our work shows, that EXD2 is a uniquely versatile mammalian exonuclease able to bind and degrade various DNA and RNA substrates. We demonstrate that loss of EXD2 in cancer cells leads to alterations in mtDNA, various metabolic changes and aberrant hypoxia signaling. We also describe how, in vivo, this leads to inhibition of breast tumor growth and increased lifespan in fruitflies. Taken together, our observations provide a link between mitochondrial nucleic acid maintenance and large-scale metabolic alterations influencing tumor growth and aging.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/328716
url http://hdl.handle.net/10803/328716
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 218 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403082991861760
score 15.301629

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