Based on a study I read, or rather skimmed. The problem of aging (stem) cells explained (1):
A significant increase in the frequency of respiratory chain deficient colonic crypts with age correlates with the frequency of mutations detected by [next generation sequencing]But to this day we do not know why deletions accumulate in muscle and point mutations in the colonic epithelium.
Mechanism of Action (1): Speculation
Mathematical modelling studies have suggested that clonal expansion of mtDNA mutations within an individual cell is likely to be due to random genetic drift and predict that it can take at least 20 years for an mtDNA mutation to clonally expand to high levels sufficient to cause COX deficiency –....Previously we examined colonic epithelial tissue from a similar ageing mouse colony and showed that clonal expansion of mtDNA mutations was a very rare event in these animals compared with aged humans . This may explain the species differences in these data, consistent with modelling studies that emphasise the difficulty of generating clonal expansion through random drift in short-lived animals .The question is if COX negative mutations are additionally selected for, like in muscle? (2) If not, then why? Induction of mitochondrial biogenesis could definitely answer this question in a mouse model. If I had to speculate, I guess, the aetiopathogenesis might really be completely different between muscle and colonic mitochondrial dysfunction. Perhaps, the reason is that substantia nigra and muscle rely on OXPHOS (aerobic) whereas stem cells do not, thus deletions in muscle would not trigger a vicious cycle as in (2)?
The pattern of somatic mtDNA mutations detected in the buccal epithelium was similar to those in the colonic epithelium. The mtDNA mutations detected were base transitions and were randomly located throughout the genome.If there is no preference for coding regions, I do think this favours clonal expanions by genetic drift.
1. PLoS Genet. 2014 Sep 18;10(9):e1004620. doi: 10.1371/journal.pgen.1004620. eCollection 2014.
Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.
Greaves LC1, Nooteboom M2, Elson JL3, Tuppen HA2, Taylor GA2, Commane DM4, Arasaradnam RP4, Khrapko K5, Taylor RW2, Kirkwood TB6, Mathers JC7, Turnbull DM1.
2. PLoS One. 2013;8(3):e59006. doi: 10.1371/journal.pone.0059006. Epub 2013 Mar 13. Mitochondrial biogenesis drives a vicious cycle of metabolic insufficiency and mitochondrial DNA deletion mutation accumulation in aged rat skeletal muscle fibers. Herbst A, Johnson CJ, Hynes K, McKenzie D, Aiken JM.