Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice

Background: Aging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established. Methodology/Principal Findings: We i...

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Autores: Hiona, Asimina, Sanz, Alberto, Kujoth, Gregory C., Pamplona Gras, Reinald, Seo, Arnold Y., Hofer, Tim, Someya, Shinichi, Miyakawa, Takuya, Nakayama, Chie, Samhan-Arias, Alejandro K., Servais, Stephane, Barger, Jamie L., Portero Otín, Manuel, Tanokura, Masaru, Prolla, Tomas A., Leeuwenburgh, Christiaan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/30325
Acceso en línea:https://doi.org/10.1371/journal.pone.0011468
http://hdl.handle.net/10459.1/30325
Access Level:acceso abierto
Palabra clave:ADN mitocondrial
Mutació (Biologia)
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spelling Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator miceHiona, AsiminaSanz, AlbertoKujoth, Gregory C.Pamplona Gras, ReinaldSeo, Arnold Y.Hofer, TimSomeya, ShinichiMiyakawa, TakuyaNakayama, ChieSamhan-Arias, Alejandro K.Servais, StephaneBarger, Jamie L.Portero Otín, ManuelTanokura, MasaruProlla, Tomas A.Leeuwenburgh, ChristiaanADN mitocondrialMutació (Biologia)Background: Aging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established. Methodology/Principal Findings: We investigated the relationship between mtDNA mutations and sarcopenia at the gene expression and biochemical levels using a mouse model that expresses a proofreading-deficient version (D257A) of the mitochondrial DNA Polymerase c, resulting in increased spontaneous mtDNA mutation rates. Gene expression profiling of D257A mice followed by Parametric Analysis of Gene Set Enrichment (PAGE) indicates that the D257A mutation is associated with a profound downregulation of gene sets associated with mitochondrial function. At the biochemical level, sarcopenia in D257A mice is associated with a marked reduction (35–50%) in the content of electron transport chain (ETC) complexes I, III and IV, all of which are partly encoded by mtDNA. D257A mice display impaired mitochondrial bioenergetics associated with compromised state-3 respiration, lower ATP content and a resulting decrease in mitochondrial membrane potential (Dym). Surprisingly, mitochondrial dysfunction was not accompanied by an increase in mitochondrial reactive oxygen species (ROS) production or oxidative damage. Conclusions/Significance: These findings demonstrate that mutations in mtDNA can be causal in sarcopenia by affecting the assembly of functional ETC complexes, the lack of which provokes a decrease in oxidative phosphorylation, without an increase in oxidative stress, and ultimately, skeletal muscle apoptosis and sarcopenia.Public Library of Science (PLoS)2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1371/journal.pone.0011468http://hdl.handle.net/10459.1/30325reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a https://doi.org/10.1371/journal.pone.0011468PLoS ONE, 2010, vol. 5, núm. 7, e11468cc-by, (c) Hiona et al., 2010info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/2.5/es/deed.caoai:repositori.udl.cat:10459.1/303252026-06-24T12:42:17Z
dc.title.none.fl_str_mv Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
title Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
spellingShingle Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
Hiona, Asimina
ADN mitocondrial
Mutació (Biologia)
title_short Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
title_full Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
title_fullStr Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
title_full_unstemmed Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
title_sort Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
dc.creator.none.fl_str_mv Hiona, Asimina
Sanz, Alberto
Kujoth, Gregory C.
Pamplona Gras, Reinald
Seo, Arnold Y.
Hofer, Tim
Someya, Shinichi
Miyakawa, Takuya
Nakayama, Chie
Samhan-Arias, Alejandro K.
Servais, Stephane
Barger, Jamie L.
Portero Otín, Manuel
Tanokura, Masaru
Prolla, Tomas A.
Leeuwenburgh, Christiaan
author Hiona, Asimina
author_facet Hiona, Asimina
Sanz, Alberto
Kujoth, Gregory C.
Pamplona Gras, Reinald
Seo, Arnold Y.
Hofer, Tim
Someya, Shinichi
Miyakawa, Takuya
Nakayama, Chie
Samhan-Arias, Alejandro K.
Servais, Stephane
Barger, Jamie L.
Portero Otín, Manuel
Tanokura, Masaru
Prolla, Tomas A.
Leeuwenburgh, Christiaan
author_role author
author2 Sanz, Alberto
Kujoth, Gregory C.
Pamplona Gras, Reinald
Seo, Arnold Y.
Hofer, Tim
Someya, Shinichi
Miyakawa, Takuya
Nakayama, Chie
Samhan-Arias, Alejandro K.
Servais, Stephane
Barger, Jamie L.
Portero Otín, Manuel
Tanokura, Masaru
Prolla, Tomas A.
Leeuwenburgh, Christiaan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ADN mitocondrial
Mutació (Biologia)
topic ADN mitocondrial
Mutació (Biologia)
description Background: Aging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established. Methodology/Principal Findings: We investigated the relationship between mtDNA mutations and sarcopenia at the gene expression and biochemical levels using a mouse model that expresses a proofreading-deficient version (D257A) of the mitochondrial DNA Polymerase c, resulting in increased spontaneous mtDNA mutation rates. Gene expression profiling of D257A mice followed by Parametric Analysis of Gene Set Enrichment (PAGE) indicates that the D257A mutation is associated with a profound downregulation of gene sets associated with mitochondrial function. At the biochemical level, sarcopenia in D257A mice is associated with a marked reduction (35–50%) in the content of electron transport chain (ETC) complexes I, III and IV, all of which are partly encoded by mtDNA. D257A mice display impaired mitochondrial bioenergetics associated with compromised state-3 respiration, lower ATP content and a resulting decrease in mitochondrial membrane potential (Dym). Surprisingly, mitochondrial dysfunction was not accompanied by an increase in mitochondrial reactive oxygen species (ROS) production or oxidative damage. Conclusions/Significance: These findings demonstrate that mutations in mtDNA can be causal in sarcopenia by affecting the assembly of functional ETC complexes, the lack of which provokes a decrease in oxidative phosphorylation, without an increase in oxidative stress, and ultimately, skeletal muscle apoptosis and sarcopenia.
publishDate 2010
dc.date.none.fl_str_mv 2010
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1371/journal.pone.0011468
http://hdl.handle.net/10459.1/30325
url https://doi.org/10.1371/journal.pone.0011468
http://hdl.handle.net/10459.1/30325
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.1371/journal.pone.0011468
PLoS ONE, 2010, vol. 5, núm. 7, e11468
dc.rights.none.fl_str_mv cc-by, (c) Hiona et al., 2010
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/2.5/es/deed.ca
rights_invalid_str_mv cc-by, (c) Hiona et al., 2010
http://creativecommons.org/licenses/by/2.5/es/deed.ca
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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