Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations.

Tianhong Su,John P Grady,Stuart Ac Mcdonald,Doug M Turnbull,Laura C Greaves,Robert W Taylor,Sorena Afshar

doi:10.1002/path.5156

Tianhong Su, John P Grady + Show 5 more

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https://doi.org/10.1002/path.5156

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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.

Highlights

Mitochondria are ubiquitous organelles present in eukaryotic cells, a major function of which is to generate ATP via the process of oxidative phosphorylation (OXPHOS)
MtDNA mutation load in epithelial crypts compared with smooth muscle fibres The load of the m.3243A>G mutation was lower in crypts laser-microdissected from the mucosa compared with fibres from the smooth muscle in oesophagus (p < 0.0001, Mann–Whitney U-test), stomach (p < 0.0001, unpaired t-test), the small intestines (SI) (p < 0.05 for patient 1 and p < 0.0001 for patient 2, unpaired t-test and Mann–Whitney U-test respectively), and colon (p < 0.005, unpaired t-test) (Figure 1B)
NDUFB8 was Understanding the behaviour of Mitochondria contain their own DNA (mtDNA) mutations in different tissues is critical to understanding the phenotype of inherited mtDNA disease and in our understanding of the impact of acquired mtDNA mutations seen in human ageing

Summary

Introduction

Mitochondria are ubiquitous organelles present in eukaryotic cells, a major function of which is to generate ATP via the process of oxidative phosphorylation (OXPHOS). Mitochondria contain their own DNA (mtDNA), which encodes 13 essential protein subunits of the OXPHOS system, 22 tRNAs and 2 rRNAs. Each cell contains multiple copies of mtDNA. In patients with primary heteroplasmic mtDNA disease, despite uniform mutation load across all tissues during foetal development [6–8], some mtDNA mutations show a decrease in the mutation load with age in blood and a few epithelial tissues [9–11] This suggests that mitotic tissue may selectively lose inherited mtDNA mutations over time. We compared OXPHOS activity, mitochondrial protein expression, and mutation load in the epithelium and smooth muscle of the oesophagus, stomach, and the small and large intestines of patients with the common inherited m.3243A>G mtDNA variant within MT-TL1 (encoding mitochondrial tRNALeu(UUR)) and m.8344A>G mtDNA variant within MT-TK (encoding mitochondrial tRNALys)

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