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

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 μM) 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 Ca²⁺-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.