title: Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice.
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.
  
  
  RESULTS
  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 gamma, 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 (Deltapsim). Surprisingly, mitochondrial dysfunction was not accompanied by an increase in mitochondrial reactive oxygen species (ROS) production or oxidative damage.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Biology of Aging, Department of Aging and Geriatric Research, Institute on Aging, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Asimina
authors.initials: A
authors.lastname: Hiona
authors.forename: Alberto
authors.initials: A
authors.lastname: Sanz
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Kujoth
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Arnold Y
authors.initials: AY
authors.lastname: Seo
authors.forename: Tim
authors.initials: T
authors.lastname: Hofer
authors.forename: Shinichi
authors.initials: S
authors.lastname: Someya
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Chie
authors.initials: C
authors.lastname: Nakayama
authors.forename: Alejandro K
authors.initials: AK
authors.lastname: Samhan-Arias
authors.forename: Stephane
authors.initials: S
authors.lastname: Servais
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Barger
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otín
authors.forename: Masaru
authors.initials: M
authors.lastname: Tanokura
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055948:Sarcopenia / Q000235:genetics* / Q000473:pathology*
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D053148:Caspase 3; D053453:Caspase 9