1. Department of Medical Nutrition, Karolinska Institutet, Novum, Karolinska University Hospital, S-141 86 Stockholm, Sweden
2. Department of Biosciences, Karolinska Institutet, Novum, Karolinska University Hospital, S-141 86 Stockholm, Sweden
3. Institute of Medical Technology and Tampere University Hospital, FIN-33014 University of Tampere, Finland
4. Astra Zeneca R&D, S-431 83 Mölndal, Sweden
5. Department of Pathology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden
6. Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden

Correspondence to: Nils-Göran Larsson^1,2 Email: nils-goran.larsson@mednut.ki.se

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 ageing^{7, 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.

1. Department of Medical Nutrition, Karolinska Institutet, Novum, Karolinska University Hospital, S-141 86 Stockholm, Sweden
2. Department of Biosciences, Karolinska Institutet, Novum, Karolinska University Hospital, S-141 86 Stockholm, Sweden
3. Institute of Medical Technology and Tampere University Hospital, FIN-33014 University of Tampere, Finland
4. Astra Zeneca R&D, S-431 83 Mölndal, Sweden
5. Department of Pathology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden
6. Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden

Correspondence to: Nils-Göran Larsson^1,2 Email: nils-goran.larsson@mednut.ki.se

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