(Not a new article, but thought-provoking)
- The PolG mutator mouse accumulates single nucleotide polymorphisms in its mtDNA and shows premature ageing phenotypes
- The threshold effect states that heteroplasmy must reach very high levels before a phenotype is shown. Although each molecule of mtDNA will possess several mutations, the activity of several mitochondrial enzymes are unaffected (whilst others such as Complex IV show activities of about 35%). In this sense, mtDNA mutations can be thought of as recessive.
- The authors here suggest that an accumulation of reactive oxygen species from a diversity of different mutations could explain how the mutator mouse displays premature ageing phenotypes.
- Endurance exercise is able to rescue the mutator phenotype in large part
- Somatic tissues and the stem cell pool suffer from oxidative stress in PolG mice. Anti-oxidants have been shown to ameliorate some phenotypes of the mutator mouse.
- Mitochondrial ROS induces telomere erosion
- ROS (in particular, hydroxyl free radicals) can react with the nucleotide guanine to form 8-OHdG. This is a marker of oxidative stress, and is referred to by the authors as "non-mutational oxidative DNA damage). In the PolG mutator mouse, endurance exercised mice have lower 8-OHdG levels by ~x3.
- A muscle-specific knockout of p53 abolishes the amelioration of the PolG phenotype by exercise. Importantly, p53 is a mtDNA repair protein, and can repair oxidative damage.
- The authors also highlight that non-mutational mtDNA damage (e.g. 8-OHdG) can be converted into spurious mutations during PCR amplification
- Note that the transcription machinery of the cell is also prone to making mistakes at sites of oxidative DNA damage
- The authors revive the idea of the classical "vicious cycle" of mtDNA damage (mtDNA damage -> ROS -> more mtDNA damage) but instead of nucleotide substitutions the authors suggest that non-mutational mtDNA damage could be a potentially explanatory hypothesis.
- Furthermore, the authors suggest that mitochondria compete with the nucleus for p53 during oxidative stress: mtDNA damage -> ROS -> nuclear DNA damage -> translocation of p53 to nucleus -> prevention of mtDNA repair -> mtDNA damage. The authors label this a "malicious cycle"
- The authors suggest that exercise promotes PGC-1a, which promotes the expression of antioxidants, which lowers the rate of nuclear DNA damage, allowing p53 to leave the nucleus.
- In the "malicious cycle" hypothesis, the authors speculate that ROS induces nuclear DNA damage, causing p53 to translocate to the nucleus, meaning that mtDNA is repaired less. So implicit to this assumption is that the nucleus takes higher precedence over mtDNA in the context of oxidative stress. If so, that's interesting. Why not upregulate p53 so that it is not limiting, and both the nucleus and mtDNA can be repaired?