ZIDOVUDINE AND DIDEOXYNUCLEOSIDES DEPLETE WILD-TYPE MITOCHONDRIAL-DNALEVELS AND INCREASE DELETED MITOCHONDRIAL-DNA LEVELS IN CULTURED KEARNS-SAYRE SYNDROME FIBROBLASTS

Keams-Sayre syndrome is the most commonly diagnosed mitochondrial cyto pathy and produces severe neuromuscular symptoms. The most frequent ca use is a mitochondrial DNA deletion that removes a 4977-base pair segm ent 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 depleti on of wild-type mtDNA while increasing the levels of deleted mitochond ria DNA in Kearns-Sayre syndrome fibroblasts. The result of these effe cts is a large increase in the relative amounts of Delta mtDNA in comp arison to wild type mtDNA. We found that Kearns-Sayre syndrome fibrobl asts are a mixed population of cells with deleted mtDNA comprising fro m 0 to over 20% of the total mtDNA in individual cells. Treatment of c loned cell lines with dideoxycytidine did not result in increased leve ls of Delta mtDNA. The results suggest that nucleoside analogs may act to increase the average Delta mtDNA levels in a mixed population of c ells by preferentially inhibiting the proliferation of cells with litt le or no Delta mtDNA, This raises the possibility that modulation of d eleted mtDNA levels may occur by similar mechanisms in vivo, in respon se to the influence of exogenous agents.