Zidovudine and dideoxynucleosides deplete wild-type mitochondrial DNA levels and increase deleted mitochondrial DNA levels in cultured Kearns-Sayre syndrome fibroblasts.
Kearns-Sayre syndrome is the most commonly diagnosed mitochondrial cytopathy and produces severe neuromuscular symptoms. The most frequent cause is a mitochondrial DNA deletion that removes a 4977-base pair segment of DNA that includes several genes encoding for respiratory chain subunits. Treatment of AIDS patients with nucleoside analogs has been reported to cause mtDNA depletion and myopathies. Here, we report that azidothymidine, dideoxyguanosine, and dideoxycytidine cause a depletion of wild-type mtDNA while increasing the levels of deleted mitochondria DNA in Kearns-Sayre syndrome fibroblasts. The result of these effects is a large increase in the relative amounts of delta mtDNA in comparison to wild type mtDNA. We found that Kearns-Sayre syndrome fibroblasts are a mixed population of cells with deleted mtDNA comprising from 0 to over 20% of the total mtDNA in individual cells. Treatment of cloned cell lines with dideoxycytidine did not result in increased levels of delta mtDNA. The results suggest that nucleoside analogs may act to increase the average delta mtDNA levels in a mixed population of cells by preferentially inhibiting the proliferation of cells with little or no delta mtDNA. This raises the possibility that modulation of deleted mtDNA levels may occur by similar mechanisms in vivo, in response to the influence of exogenous agents.
Wang
H
H
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Lemire
B D
BD
Cass
C E
CE
Weiner
J H
JH
Michalak
M
M
Penn
A M
AM
Fliegel
L
L
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000494:pharmacology*; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion; D016047:Zalcitabine / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D015215:Zidovudine; D016047:Zalcitabine; C050220:2',3'-dideoxyguanosine