Mitochondrial dysfunction and mitochondrial DNA damage are significant features of aging. One of the tools used to investigate the role of mitochondria in aging is the lineage of mitochondrial mutator mice. These mice accumulate mutations in mitochondrial DNA quite rapidly, and exhibit accelerated aging. Setting aside the discussion of what exactly qualifies as accelerated aging, researchers here present evidence to suggest that the mitochondrial mutation is not the cause of accelerated aging in this model. Instead, this particular approach to accelerating mitochondrial DNA damage leads in addition to accelerated nuclear DNA damage. This is consistent with the many other forms of accelerated aging that are caused by breakage of DNA repair mechanisms, and thus faster accumulation of unrepaired mutation in nuclear DNA.
The conclusion here is that mitochondrial mutator mice are a poor model, possibly just this model, possibly the entire class of such models as they stand, not that mitochondria are less relevant to aging. There is far and away too much evidence to dismiss mitochondrial damage and dysfunction as a cause of degenerative aging. If anything, this brings the mutator mice in line with other mouse lineages with high levels of mitochondrial mutation, as those do not display accelerated aging - their mechanisms of breakage are presumably not significantly impacting nuclear DNA mutation rates.
Mitochondria are small powerhouse organelles that have their own DNA, the mitochondrial DNA (mtDNA). For almost half a century, mitochondrial DNA mutations and oxidative stress have been asserted as major contributors to aging, as postulated in the mitochondrial theory of aging published in the 1970s. The theory has been tested on the mtDNA Mutator mice that have an inactive DNA repair mechanism. These mice accumulate mtDNA mutations and present with accelerated aging, which has led scientists to believe that mtDNA mutagenesis drives aging. However, despite rigorous studies by several groups, no one has been able to show that the Mutator mice would present elevated oxidative stress.
The prematurely-ageing Mutator mice harbour a defective polymerase-gamma enzyme and present with pronounced mtDNA mutagenesis. Despite the existence of other mouse models with equivalent mtDNA mutagenic propensity, the Mutator mouse model is the only one manifesting accelerated aging. Furthermore, progeria is not a clinical feature of mitochondrial disease patients, not even in those with the most severe mtDNA mutagenic profiles. Rather, the clinical picture of the mtDNA Mutator mice is remarkably similar to that of other mouse progeria models and human progeric syndromes with nuclear genome instability, with the most prominent defects in proliferating cells, and especially in stem cells and progenitor cells important for tissue regeneration.
The new study shows that in addition to the mtDNA maintenance defects, the Mutator mice also manifest nuclear DNA defects, including replication fork stalling, increased DNA-breaks and activation of DNA damage response pathways. So, how can a primary mitochondrial DNA maintenance defect affect the maintenance of nuclear genome? Nucleotides are the building blocks of DNA, and proper cellular nucleotide levels are critical for genome maintenance. Moreover, the cytoplasmic and mitochondrial nucleotide pools are interconnected. The researchers show that in the Mutator mice, the total cellular nucleotide levels are decreased, while the mitochondrial nucleotide pools are increased, suggesting preferential usage of nucleotides in the mitochondria. Indeed, the replication of mtDNA is drastically accelerated in the cells of the Mutator mice.