Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Carla Giordano^*, Mariangela Sebastiani^*, Roberto De Giorgio, Claudia Travaglini^*, Andrea Tancredi, Maria Lucia Valentino, Marzio Bellan, Andrea Cossarizza^¶, Michio Hirano^||, Giulia d'Amati^* and Valerio Carelli

From the Dipartimento di Medicina Sperimentale,^* Sapienza, Universià’ di Roma, Rome, Italy; Department of Internal Medicine & Gastroenterology, University of Bologna; Dipartimento di Scienze Neurologiche, Universita’ di Bologna, Bologna, Italy; Dipartimento di Studi Geoeconomici, Sapienza, Università di Roma, Rome Italy; Dipartimento di Scienze Biomediche,^¶ Sezione di Patologia Generale, Universita’ di Modena e Reggio Emilia, Italy; Columbia University Medical Center,|| New York, New York

Chronic intestinal pseudo-obstruction is a life-threateningcondition of unknown pathogenic mechanisms. Chronic intestinalpseudo-obstruction can be a feature of mitochondrial disorders,such as mitochondrial neurogastrointestinal encephalomyopathy(MNGIE), a rare autosomal-recessive syndrome, resulting frommutations in the thymidine phosphorylase gene. MNGIE patientsshow elevated circulating levels of thymidine and deoxyuridine,and accumulate somatic mitochondrial DNA (mtDNA) defects. Thepresent study aimed to clarify the molecular basis of chronicintestinal pseudo-obstruction in MNGIE. Using laser capturemicrodissection, we correlated the histopathological featureswith mtDNA defects in different tissues from the gastrointestinalwall of five MNGIE and ten control patients. We found mtDNAdepletion, mitochondrial proliferation, and smooth cell atrophyin the external layer of the muscularis propria, in the stomachand in the small intestine of MNGIE patients. In controls, thelowest amounts of mtDNA were present at the same sites, as comparedwith other layers of the gastrointestinal wall. We also observedmitochondrial proliferation and mtDNA depletion in small vesselendothelial and smooth muscle cells. Thus, visceral mitochondrialmyopathy likely causes gastrointestinal dysmotility in MNGIEpatients. The low baseline abundance of mtDNA molecules maypredispose smooth muscle cells of the muscularis propria externallayer to the toxic effects of thymidine and deoxyuridine, andexposure to high circulating levels of nucleosides may accountfor the mtDNA depletion observed in the small vessel wall.