AZT causes tissue-specific inhibition of mitochondrial bioenergetic function.
The mitochondrial myopathy associated with long-term AZT therapy is a factor that limits the clinical efficacy of this compound in the treatment of AIDS. The biochemical basis for this tissue-specific pathology was investigated by measuring the effect of AZT on various aspects of bioenergetic function in mitochondria isolated from rat skeletal muscle, brain, and liver. AZT induced a dose-dependent inhibition of both NADH-linked respiration in intact mitochondria and NADH-cytochrome c reductase activity (but not succinate-cytochrome c reductase activity) in freeze-thawed mitochondrial preparations isolated from all three tissue types (1/2 maximal inhibition was obtained at 2 mg/ml and between 0.3 and 0.8 mg/ml AZT, respectively). These data demonstrate that high concentrations of AZT inhibit electron transfer through respiratory enzyme complex I. Moreover, AZT was shown to induce a tissue-specific inhibition of succinate-linked respiration in intact mitochondria isolated from rat skeletal muscle (1/2 maximal inhibition at 0.5 mg/ml AZT) and possibly brain, but not liver. The data suggest that this inhibition possibly occurs at the level of succinate transport. These results may help to explain the tissue-specific mitochondrial effects that are induced by long-term zidovudine treatment of AIDS patients and suggest that the anti-retroviral activity exhibited by AZT may be distinct from its mechanism of mitochondrial toxicity.
Modica-Napolitano
J S
JS
Tufts University, Department of Biology, Medford, MA 02155.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002458:Cell Fractionation / Q000379:methods; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007700:Kinetics; D008293:Malates / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology*
D005971:Glutamates; D008293:Malates; D018698:Glutamic Acid; D015215:Zidovudine; D013384:Succinate Cytochrome c Oxidoreductase; D009245:NADH Dehydrogenase