One of the major challenges in aging research is establishing the relative importance of the various well-known different mechanisms, hallmarks, and dysfunctions of aging. This is large part because biological systems and their relationships to one another are not fully mapped and understood at the detail level. Mitochondrial dysfunction is a great example; mitochondria are enormously complex, and even very important processes such as mitophagy are not completely understood in detail. Thus there is considerable debate over the importance of mitochondrial DNA damage to aging.
One of the pillars of supporting evidence for the importance of mitochondrial DNA damage in aging comes from the harmful effects of mutated mitochondrial DNA polymerase gamma (POLG) in mice. This genetic change impairs mitochondrial DNA maintenance machinery in a way that produces a large burden of mutations in mitochondrial DNA, loss of mitochondrial function, and accelerated measures of aging and age-related disease. In today's open access paper, researchers produce a similar burden of mitochondrial DNA in mice without the full presence of the disabling mutation in POLG - and these animals do not exhibit the expected dramatic loss of mitochondrial function. This lets us hypothesize that other functions of POLG are important in mitochondrial function, and undermines the argument for the importance of stochastic mitochondrial DNA damage.
Mitochondrial DNA (mtDNA) mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear.
Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced.
To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal.
These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.
View the full article at FightAging
