2',3'-Dideoxycytidine alters calcium buffering in cultured dorsal root ganglion neurons

JL Werth, B Zhou, LM Nutter and SA Thayer

Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.

Mitochondria play a prominent role in shaping intracellular calcium concentration ([Ca2+]i) transients in dorsal root ganglion neurons. Mitochondrial DNA polymerase is inhibited by antiviral compounds such as 2',3'-dideoxycytidine (ddC). Here, we test the hypothesis that ddC can alter mitochondrially mediated Ca2+ buffering in neurons. Chronic treatment of dorsal root ganglion cultures with ddC (1 microM) lowered mitochondrial DNA levels and decreased the mitochondrially mediated component of depolarization-induced [Ca2+]i transients. The inhibition increased in a time-dependent manner, reaching a maximum at 6 days. ddC did not affect small, action potential-evoked, [Ca2+]i transients that are predominantly buffered by Ca(2+)-ATPases, suggesting that ATP levels were not depleted. The drug did not inhibit whole-cell Ca2+ currents, indicating that the Ca2+ load was not affected. Thus, ddC produces a graded, time-dependent inhibition of mitochondrial function that is reflected, in part, by a decrease in the direct buffering of Ca2+ by mitochondria. This effect may contribute to the peripheral neuropathy that results from ddC treatment. Furthermore, ddC promises to be a useful tool to study the role of mitochondria in [Ca2+]i homeostasis and neurodegenerative processes.

Volume 45, Issue 6, pp. 1119-1124, 06/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics