Thursday, 25 June 2015

Mitochondrial DNA: Radically free of free-radical driven mutations

The "vicious circle" idea that mitochondria produce ROS, which damage mtDNA, leading to the production of poorer mitochondrial machines which produce more ROS, is often mentioned in the context of ageing and other time-worsening conditions. But -- as we heard at the excellent MiP school at UCL -- claiming "ROS do damage" without considering the source and specific nature of the species, and the location and mechanism of the damage, can be dangerously misleading. This illuminating review looks in some detail at the processes that would have to occur for mitochondrially-produced ROS to damage mtDNA. Turns out that the physical separation of the ETC from mtDNA and the complexity of the chemical pathways required mean that ROS damage to mtDNA is unlikely to be a key player; a finding borne out by an increasing volume of experiments looking at, for example, mutational signatures in mtDNA, which are also discussed. Attention is also drawn to the fact that mtDNA has reasonably robust repair mechanisms. Instead, it's more likely that errors during replication account for mtDNA damage.

In the final parts of the paper the authors look at the behaviour of mixed mtDNA populations. They suggest that random drift dominates such behaviour, as opposed to selective differences (which they acknowledge but assign a lesser role). This could be argued against: recent work in humans [1] (which the authors reference) and mice [2] (which they don't) shows fairly strong and common signals of selective differences between non-pathological mtDNA variants. But they do say that further work is necessary to characterise segregation patterns, which is certainly true.


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