Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant
Boschetti, Elisa (IRCCS Azienda Ospedaliero-Universitaria di Bologna)
Caporali, Leonardo (IRCCS Istituto delle Scienze Neurologiche di Bologna)
D'Angelo, Roberto (IRCCS Azienda Ospedaliero-Universitaria di Bologna)
Malagelada Prats, Carolina (Hospital Universitari Vall d'Hebron)
Accarino, Ana María (Hospital Universitari Vall d'Hebron)
Dotti, Maria Teresa (University of Siena)
Costa, Roberta (University of Bologna)
Cenacchi, Giovanna (IRCCS Azienda Ospedaliero-Universitaria di Bologna)
Pironi, Loris (University of Bologna)
Rinaldi, Rita (IRCCS Azienda Ospedaliero-Universitaria di Bologna)
Stanghellini, Vincenzo (University of Bologna)
Ratti, Stefano (University of Bologna)
Manzoli, Lucia (University of Bologna)
Carelli, Valerio (IRCCS Istituto delle Scienze Neurologiche di Bologna)
De Giorgio, Roberto (University of Ferrara)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	Mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Gastrointestinal degeneration ; Microanatomical dissection ; Mitochondrial disorders ; MNGIE ; MtDNA depletion
Published in:	International journal of molecular sciences, Vol. 23 (august 2022) , ISSN 1422-0067

DOI: 10.3390/ijms23158792
PMID: 35955927

10 p, 2.5 MB

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