Chronic
intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic
intestinal pseudo-obstruction can be a feature of
mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the
thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of
thymidine and
deoxyuridine, and accumulate somatic
mitochondrial DNA (
mtDNA) defects. The present study aimed to clarify the molecular basis of chronic
intestinal pseudo-obstruction in MNGIE. Using
laser capture microdissection, we correlated the histopathological features with
mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found
mtDNA depletion, mitochondrial proliferation, and smooth cell
atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of
mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and
mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral
mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of
mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of
thymidine and
deoxyuridine, and exposure to high circulating levels of
nucleosides may account for the
mtDNA depletion observed in the small vessel wall.