Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1 a, p53, and DNA damage. A hypothesis

Safdar A, Annis S, Kraytsberg Y, Laverack C, Saleem A, Popadin K, Woods DC, Tilly JL, Khrapko K

https://www.sciencedirect.com/science/article/pii/S0959437X16300855?via%3Dihub

(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. 

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Thoughts

• 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?

So Happy Together: The Storied Marriage Between Mitochondria and the Mind.

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(18)31316-7/fulltext

Ruth F. McCan, David A. Ross

Many neuronal functions need mitochondria. Therefore, one would expect mitochondrial damage to to affect the nervous system. Indeed, we see a higher than normal incidence of psychiatric illnesses in people with genetic mitochondrial disorders and depressive episodes have been observed in mouse model of genetic mitochondrial diseases.

Another area of research is exploring the other direction of causality: can psychological stress and depression cause mitochondrial dysfunctions?

One proposed mechanism involves glucocorticoids. Experiments with cultured mouse neurons suggest that mitochondria are impaired by long-term exposure to glucocorticoids, which may be overproduced in states of stress and depression.

Another hypothesis involves oxidative stress (OS), caused by reactive oxygen species (ROS), which are produced by mitochondria. Biomarkers of OS are increased in people with depression, and other mood and anxiety disorders seem associated to OS. It might be that stress leads to a hyper-metabolic state in which mitochondria produce more ROS. These are toxic to mitochondria themselves, which are very vulnerable to oxidative damage, potentially causing more ROS production in a vicious cycle.

A study highlighting potential connections between stress, depression and mitochondria was published in 2015 by Cai et al., who collaborated with more than 60 scientists to look at a cohort of 11,670 women from China, through whole-genome sequencing of saliva samples.

It was found that women who had experienced stressful life events and depression had shortened telomeres, something which can be seen in settings of OS. It might be that stress acts on mitochondria, triggering a cascade which leads to depression. However, another possible explanation can be that stress take people who are more prone to depression and triggers an overdrive state in which mitochondria become overwhelmed, leading to OS. Therefore, it is not clear whether mitochondrial dysfunctions cause stress or the other way around.

Another question which is attracting interest concerns our mitochondria are involved in synaptic health and dysfunction in depression. It is thought that in depression neurons atrophy, synapses vanish and dendrites shrink. Although it is not clear whether or not (and how) these morphological changes are causally connected to the disease, it is worth considering the underlying mechanism. It is easy to imagine that large amounts of energy are required to create new neurons and synapses, so it is likely that mitochondria play a role. Moreover, mitochondria are involved in the regulation of intracellular calcium leves, which is crucial at synapses, since calcium stimulates neurotransmitter release.

It is clear that the more we learn about mitochondria, the more they can help unravel the connections between neurotransmitters, mood states, genetic diseases and psychiatric symptoms, life experiences and mental health.