Premature ageing in mice expressing defective mitochondrial DNA polymerase.
Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. 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. 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.
Trifunovic
Aleksandra
A
Department of Medical Nutrition, Karolinska Institutet, Novum, Karolinska University Hospital, S-141 86 Stockholm, Sweden.
Wredenberg
Anna
A
Falkenberg
Maria
M
Spelbrink
Johannes N
JN
Rovio
Anja T
AT
Bruder
Carl E
CE
Bohlooly-Y
Mohammad
M
Gidlöf
Sebastian
S
Oldfors
Anders
A
Wibom
Rolf
R
Törnell
Jan
J
Jacobs
Howard T
HT
Larsson
Nils-Göran
NG
D000273:Adipose Tissue; D019588:Aging, Premature / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000505:Alopecia / Q000150:complications / Q000201:enzymology / Q000235:genetics; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D015519:Bone Density / Q000235:genetics; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D006720:Homozygote; D007738:Kyphosis / Q000150:complications / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D019076:Transgenes / Q000235:genetics
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse