Premature ageing in mice expressing defective mitochondrial DNA polymerase

Aleksandra Trifunovic, Anna Wredenberg, Maria Falkenberg, Johannes N. Spelbrink, Anja T. Rovio, Carl E. Bruder, Mohammad Bohlooly-Y, Sebastian Gidlöf, Anders Oldfors, Rolf Wibom, Jan Törnell, Howard T. Jacobs and Nils-Göran Larsson ()
Additional contact information
Aleksandra Trifunovic: Karolinska Institutet, Novum, Karolinska University Hospital
Anna Wredenberg: Karolinska Institutet, Novum, Karolinska University Hospital
Maria Falkenberg: Karolinska Institutet, Novum, Karolinska University Hospital
Johannes N. Spelbrink: Institute of Medical Technology and Tampere University Hospital, University of Tampere
Anja T. Rovio: Institute of Medical Technology and Tampere University Hospital, University of Tampere
Carl E. Bruder: Astra Zeneca R&D
Mohammad Bohlooly-Y: Astra Zeneca R&D
Sebastian Gidlöf: Karolinska Institutet, Novum, Karolinska University Hospital
Anders Oldfors: Sahlgrenska University Hospital
Rolf Wibom: Karolinska Institutet, Karolinska University Hospital
Jan Törnell: Astra Zeneca R&D
Howard T. Jacobs: Institute of Medical Technology and Tampere University Hospital, University of Tampere
Nils-Göran Larsson: Karolinska Institutet, Novum, Karolinska University Hospital

Nature, 2004, vol. 429, issue 6990, 417-423

Abstract: Abstract Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans1, monkeys2 and rodents3. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart4, skeletal muscle5 and brain6. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing7,8. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.

Date: 2004
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DOI: 10.1038/nature02517

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