Details

Autor(en) / Beteiligte

• Williams, Siôn L.
• Huang, Jia
• Edwards, Yvonne J.K.
• Ulloa, Rick H.
• Dillon, Lloye M.
• Prolla, Tomas A.
• Vance, Jeffery M.
• Moraes, Carlos T.
• Züchner, Stephan

Titel

The mtDNA Mutation Spectrum of the Progeroid Polg Mutator Mouse Includes Abundant Control Region Multimers

Ist Teil von

• Cell metabolism, 2010-12, Vol.12 (6), p.675-682

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• Polg mtDNA mutator mice are important models for investigating the role of acquired mtDNA mutations in aging. Despite extensive study, there remains little consensus on either the etiology of the progeroid phenotype or the mtDNA mutation spectrum induced by disrupted polymerase-γ function. To investigate the latter, we have developed a novel, pragmatic approach we term “Mito-seq,” applying next-generation sequencing to enriched, native mtDNA. Regardless of detection parameters we observed an increase of at least two orders of magnitude in the number of mtDNA single nucleotide variants in Polg mutator mice compared to controls. We found no evidence for the accumulation of canonical mtDNA deletions but multimers of the mtDNA control region were identified in brain and heart. These control region multimers (CRMs) contained heterogeneous breakpoints and formed species that excluded the majority of mtDNA genes. CRMs demonstrate that polymerase-γ 3′-5′ exonuclease activity is required for preserving mtDNA integrity. ► Mito-Seq provides a sensitive, pragmatic approach to mtDNA mutation detection ► Polg D257A/D257A mice accumulate control region multimers (CRMS) distinct from mtDNA ► CRMs are associated with a mild mtDNA depletion and increased mtDNA gene expression