Format

Send to

Choose Destination
J Pathol. 2018 Dec;246(4):427-432. doi: 10.1002/path.5156. Epub 2018 Nov 5.

Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations.

Author information

1
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
2
Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
3
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
4
LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne, UK.

Abstract

Inherited mitochondrial DNA (mtDNA) mutations cause mitochondrial disease, but mtDNA mutations also occur somatically and accumulate during ageing. Studies have shown that the mutation load of some inherited mtDNA mutations decreases over time in blood, suggesting selection against the mutation. However, it is unknown whether such selection occurs in other mitotic tissues, and where it occurs within the tissue. Gastrointestinal epithelium is a canonical mitotic tissue rapidly renewed by stem cells. Intestinal crypts (epithelium) undergo monoclonal conversion with a single stem cell taking over the niche and producing progeny. We show: (1) that there is a significantly lower mtDNA mutation load in the mitotic epithelium of the gastrointestinal tract when compared to the smooth muscle in the same tissue in patients with the pathogenic m.3243A>G and m.8344A>G mutations; (2) that there is considerable variation seen in individual crypts, suggesting changes in the stem cell population; (3) that this lower mutation load is reflected in the absence of a defect in oxidative phosphorylation in the epithelium. This suggests that there is selection against inherited mtDNA mutations in the gastrointestinal stem cells that is in marked contrast to the somatic mtDNA mutations that accumulate with age in epithelial stem cells leading to a biochemical defect. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

KEYWORDS:

MELAS; MERRF; alimentary canal; gastrointestinal epithelium; intestinal stem cell; m.3243A>G; mitochondrial DNA mutation; mitochondrial disease; segregation; selection

PMID:
30146801
PMCID:
PMC6282723
DOI:
10.1002/path.5156
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center