Mitochondrial Mutator Mice Exhibit Accelerated Nuclear DNA Damage
Mice in which the POLG genek critical to repair of mitochondrial DNA, is disabled via genetic engineering exhibit accelerated aging. Researchers here show that these mice also show an accelerated rate of nuclear DNA damage and shorter telomere length. Telomeres shorten with each cell division in somatic cells, eventually reaching the Hayflick limit and senescence or programmed cell death, while stem cells produce daughter cells with long telomeres to replace losses. Average telomere length is thus, loosely, a measure of stem cell function, though since it is normally measured in immune cells from a blood sample, it also reflects immune system stress. The raised rate of nuclear DNA strand breaks may be the more interesting correlation here, given recent work suggesting that this repeated cycles of damage and repair of this sort results in epigenetic changes characteristic of aging.
Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome.
Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondria play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.