Mitochondrial DNA Mutations Induce Mitochondrial Dysfunction, Apoptosis and Sarcopenia in Skeletal Muscle of Mitochondrial DNA Mutator Mice

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dc.contributor.author Hiona, Asimina -
dc.contributor.author Kujoth, Gregory C -
dc.contributor.author Pamplona, Reinald -
dc.contributor.author Sanz, Alberto (Tay) -
dc.date.accessioned 2012-06-17T20:14:33Z
dc.date.available 2012-06-15 07:13:02 -
dc.date.available 2012-06-17T20:14:33Z
dc.date.issued 2010 -
dc.identifier.issn 1932-6203 -
dc.identifier.uri http://tampub.uta.fi/handle/10024/65938
dc.description Public Library of Science -
dc.description.abstract 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 γ, 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 (Δψm). 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. -
dc.language.iso en -
dc.title Mitochondrial DNA Mutations Induce Mitochondrial Dysfunction, Apoptosis and Sarcopenia in Skeletal Muscle of Mitochondrial DNA Mutator Mice -
dc.type fi=Artikkeli aikakauslehdessä | en=Journal article| -
dc.identifier.urn urn:nbn:uta-3-695 -
dc.identifier.doi 10.1371/journal.pone.0011468 -
dc.type.version fi=Kustantajan versio | en=Publisher's version| -
dc.subject.okm fi=Lääketieteen bioteknologia | en=Medical biotechnology| -
dc.journal.title PLoS ONE -
dc.journal.volume 5 -
dc.journal.number 7 -
dc.journal.volumepagerange 1-19 -
dc.oldstats 44 -

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