Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice.
Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. This concept has been proven by in vitro studies over many years, but in vivo models are required to demonstrate its relevance to multicellular organisms and to human diseases. Accordingly, we have generated thymidine phosphorylase (TP) and uridine phosphorylase (UP) double knockout (TP(-/-)UP(-/-)) mice, which show severe TP deficiency, increased thymidine and deoxyuridine in tissues and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes and encephalopathy. These findings largely account for the pathogenesis of mitochondrial neurogastrointestinal encephalopathy (MNGIE), the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability.
López
Luis C
LC
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Akman
Hasan O
HO
García-Cazorla
Angeles
A
Dorado
Beatriz
B
Martí
Ramón
R
Nishino
Ichizo
I
Tadesse
Saba
S
Pizzorno
Giuseppe
G
Shungu
Dikoma
D
Bonilla
Eduardo
E
Tanji
Kurenai
K
Hirano
Michio
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000172:deficiency* / Q000235:genetics; D014543:Uridine Phosphorylase / Q000235:genetics / Q000378:metabolism*
D004272:DNA, Mitochondrial; D003854:Deoxyribonucleotides; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D042967:Electron Transport Complex I