Effect of 2',3'-dideoxycytidine on oxidative phosphorylation in the PC12 cell, a neuronal model.
Peripheral neuropathy induced by 2',3'-dideoxycytidine (ddC) could result from the previously shown inhibition of mtDNA replication by the action of ddC on the mitochondrial enzyme DNA polymerase gamma. Such inhibition would be expected to impair oxidative phosphorylation, and this was demonstrated in the present study for the PC12 cell, a model of a peripheral neuron. The dramatic rise in lactate formation upon exposure of the cell to ddC indicated that increased glycolysis was needed to produce ATP. A concomitant rise in O2 uptake indicated that oxidative phosphorylation had become uncoupled. When tested in a standard respiratory control system (isolated rat liver mitochondria), however, we found ddC not to be an uncoupler. Rather, the uncoupling most likely resulted from the failure of synthesis of one or more mitochondrial gene products necessary for oxidative phosphorylation. We also observed an important distinction between the manner in which ddC and 3'-azido-3'-deoxythymidine (AZT) act. ddC-exerted inhibition of oxidative phosphorylation was delayed for several days. This is consistent with the inhibition occurring indirectly, most likely as a result of the prior destruction of the mitochondrial genome, which encodes many of the components of the oxidative phosphorylation system. In contrast, we have shown previously that although AZT also impairs replication of the mitochondrial genome (in the Friend murine erythroleukemic cell), it also attacks directly an additional primary target leading to impairment of oxidative phosphorylation; its initial inhibition of this process is immediate, not occurring via inhibition of mitochondrial DNA replication.
Keilbaugh
S A
SA
Department of Biochemistry and Cell Biology, State University of New York, Stony Brook 11794, U.S.A.
Hobbs
G A
GA
Simpson
M V
MV
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D002455:Cell Division; D004272:DNA, Mitochondrial / Q000378:metabolism; D019344:Lactic Acid / Q000096:biosynthesis; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D016716:PC12 Cells; D051381:Rats; D016047:Zalcitabine / Q000494:pharmacology*
D000963:Antimetabolites; D004272:DNA, Mitochondrial; D019344:Lactic Acid; D016047:Zalcitabine