| Mitochondrial bioenergetic defects have been implicated in the pathology of a number of neurodegenerative diseases. Moreover, reactive metabolites generated from the oxidation of the neurotransmitter dopamine are thought to contribute to the damage to neurons of the basal ganglia. Therefore, we determined if the impairment of energy metabolism by the reversible succinate dehydrogenase inhibitor malonate would have an effect on endogenous dopamine homeostasis and conversely, if dopamine would influence the damage resulting from mitochondrial inhibition.; Using unilateral microdialysis in awake, behaving mice, we perfused malonate through a probe implanted into the left striatum. We found that the metabolic stress induced a dose-dependent efflux in striatal dopamine that correlated with toxicity to dopamine nerve terminals as determined by striatal dopamine content. In addition, the malonate-induced damage was dopamine-dependent because the depletion of dopamine prior to the insult attenuated the toxicity as well as the dopamine overflow.; Our data also demonstrated that the energy impairment by malonate disrupted endogenous dopamine storage, resulting in a decrease in striatal dopamine levels and a concomitant increase in metabolites. Furthermore, the administration of drugs that perturb dopamine homeostasis after the metabolic stress was imposed enhanced the resultant damage. Importantly, disturbances in dopamine sequestration in the absence of a metabolic stress were not toxic.; We next determined that the malonate-induced dopamine efflux from the cytosol into the synapse was via reversal of the plasma membrane dopamine transporter, a protein that normally accumulates dopamine into the cytosol. Specific inhibitors of the transporter not only blocked the neurotransmitter efflux, but also protected the dopamine nerve terminals against damage.; Parallel studies were performed in vitro in primary rat embryonic mesencephalic and striatal cultures. These data recapitulated the in vivo findings and also provided further insight into the biochemical processes that occur under metabolic stress.; Taken together, our data demonstrate that dopamine plays a role in damage under conditions of mitochondrial dysfunction. Furthermore, the regulation of dopamine homeostasis is necessary for neuronal survival. These data provide a framework for understanding the fundamental changes in dopamine flux resulting from mitochondrial impairment. |
