RT Journal Article
T1 Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy
A1 Garcia Diaz, Beatriz
A1 Garone, Caterina
A1 Barca, Emanuele
A1 Mojahed, Hamed
A1 Gutiérrez, Purificación
A1 Pizzorno, Giuseppe
A1 Tanji, Kurenai
A1 Arias Mendoza, Fernando
A1 Quinzii, Catarina M
A1 Hirano, Michio
K1 Mitocondrias
AB Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis.
PB Oxford University Press
YR 2014
FD 2014
LK https://hdl.handle.net/10630/32327
UL https://hdl.handle.net/10630/32327
LA eng
NO Beatriz Garcia-Diaz, Caterina Garone, Emanuele Barca, Hamed Mojahed, Purification Gutierrez, Giuseppe Pizzorno, Kurenai Tanji, Fernando Arias-Mendoza, Caterina M. Quinzii, Michio Hirano, Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy, Brain, Volume 137, Issue 5, May 2014, Pages 1337–1349, https://doi.org/10.1093/brain/awu068
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 21 ene 2026