Samstag, 13. Dezember 2014

Expanded Deletions vs Mutations: an unsolved Mystery

Edit (02-18-2015)
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 [37]–[39]....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 [41]. 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 [39].
The question arises if mutations leading to a COX negative phenotype are additionally selected for, like in muscle? (2) If not, then why? Induction of mitochondrial biogenesis could help to answer this question in a mouse model. If I had to speculate, I guess, the aetiopathogenesis might be completely different between muscle and colonic mitochondrial dysfunction. Perhaps substantia nigra and muscle rely more on OXPHOS (aerobic) whereas stem cells do not (4), thus deletions in muscle would not trigger a vicious cycle as in (2)?


Can drift explain the pattern of mutations?
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. I am, however, not sure if this statement refers to all clonally expanded muutations or all mutations.
Modelling by Baines et al. (Larsson and Turnbull group) suggests that in colonic crypts drift can indeed explain accumulation of deletions (5).

Would we expect mutations in ND4 if Kirkwood and Kowal are right?
K & K suggest that the product of ND4 provides negative feedback to mitochondrial DNA replication (3) and promotes expansion of deletions. Since this would promote replication of all genomes I fail to see how this can be applied to mutations.

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.3. Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):2972-7. doi:10.1073/pnas.1314970111. Epub 2014 Feb

3.Transcription could be the key to the selection advantage ofmitochondrial deletion mutants in aging.Kowald A1, Kirkwood TB.4. Various stem cells, including HSCs, mesenchymal stem cells (MSCs) and neural stem cells (NSCs), reside in a hypoxic niche.

4. "Various stem cells, including HSCs, mesenchymal stem cells (MSCs) and neural stem cells (NSCs), reside in a hypoxic niche."
Nat Rev Mol Cell Biol. 2014 Apr;15(4):243-56. doi: 10.1038/nrm3772. Metabolic requirements for the maintenance of self-renewing stem cells.
Ito K, Suda T.

5. Mech Ageing Dev. 2014 Jul;139:22-30. doi: 10.1016/j.mad.2014.06.003. Epub 2014 Jun 7.Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans.Baines HL1, Stewart JB2, Stamp C1, Zupanic A3, Kirkwood TB3, Larsson NG2, Turnbull DM4, Greaves LC5.

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