title: Down-regulation of mitochondrial thymidine kinase 2 and deoxyguanosine kinase by didanosine: implication for mitochondrial toxicities of anti-HIV nucleoside analogs.
abstract: Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial rate limiting phosphorylation of deoxynucleosides and are essential enzymes for mitochondrial function. Chemotherapy using nucleoside analogs is often associated with mitochondrial toxicities. Here we showed that incubation of U2OS cells with didanosine (ddI, 2',3'-dideoxyinosine), a purine nucleoside analog used in the highly active antiretroviral therapy (HAART), led to selective degradation of both mitochondrial TK2 and dGK while the cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) were not affected. Addition of guanosine to the ddI-treated cells prevented the degradation of mitochondrial TK2 and dGK. The levels of intracellular reactive oxygen species and protein oxidation in ddI-treated and control cells were also measured. The results suggest that down-regulation of mitochondrial TK2 and dGK may be a mechanism of mitochondrial toxicity caused by antiviral and anticancer nucleoside analogs.
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, SE-751 23 Uppsala, Sweden.
authors: Ren
authors: R
authors: Sun
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, SE-751 23 Uppsala, Sweden.
authors: Staffan
authors: S
authors: Eriksson
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, SE-751 23 Uppsala, Sweden. Electronic address: liya.wang@slu.se.
authors: Liya
authors: L
authors: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D003842:Deoxycytidine Kinase / Q000378:metabolism; D016049:Didanosine / Q000633:toxicity*; D004347:Drug Interactions; D006151:Guanosine / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D017382:Reactive Oxygen Species; D006151:Guanosine; D017853:Phosphotransferases (Alcohol Group Acceptor); C105339:thymidine kinase 2; C019165:deoxyguanosine kinase; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D003842:Deoxycytidine Kinase; D016049:Didanosine
keywords: Deoxyguanosine kinase; Mitochondrial toxicity; Nucleoside analogs; Thymidine kinase 2; ddI