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. (C) 2014 Elsevier Inc. All rights reserved.

Keywords

Thymidine kinase 2; Deoxyguanosine kinase; Nucleoside analogs; ddI; Mitochondrial toxicity

Published in

Biochemical and Biophysical Research Communications
2014, volume: 450, number: 2, pages: 1021-1026

SLU Authors

• Sun, Ren

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Eriksson, Staffan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Wang, Liya

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Cell and Molecular Biology
Cell Biology
Biochemistry and Molecular Biology

Publication identifier

• DOI: https://doi.org/10.1016/j.bbrc.2014.06.098

Permanent link to this page (URI)

https://res.slu.se/id/publ/62166