Mitochondrial deoxyribonucleoside triphosphate pools in thymidine kinase 2 deficiency.
Deficiency of mitochondrial thymidine kinase (TK2) is associated with mitochondrial DNA (mtDNA) depletion and manifests by severe skeletal myopathy in infancy. In order to elucidate the pathophysiology of this condition, mitochondrial deoxyribonucleoside triphosphate (dNTP) pools were determined in patients' fibroblasts. Despite normal mtDNA content and cytochrome c oxidase (COX) activity, mitochondrial dNTP pools were imbalanced. Specifically, deoxythymidine triphosphate (dTTP) content was markedly decreased, resulting in reduced dTTP:deoxycytidine triphosphate ratio. These findings underline the importance of balanced mitochondrial dNTP pools for mtDNA synthesis and may serve as the basis for future therapeutic interventions.
Saada
Ann
A
Metabolic Disease Unit, Shaare-Zedek Medical Center, Jerusalem, Israel. saada@szmc.org.il
Ben-Shalom
Efrat
E
Zyslin
Rivka
R
Miller
Chaya
C
Mandel
Hanna
H
Elpeleg
Orly
O
D002467:Cell Nucleus / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D017240:Mitochondrial Myopathies / Q000473:pathology; D009154:Mutation; D013937:Thymidine Kinase / Q000172:deficiency*
D004272:DNA, Mitochondrial; D003854:Deoxyribonucleotides; D003576:Electron Transport Complex IV; C105339:thymidine kinase 2; D013937:Thymidine Kinase