Mitochondria control AMPA/kainate receptor-induced cytoplasmic calcium deregulation in rat cerebellar granule cells

Although mitochondria mediate the delayed failure of cytoplasmic Ca2+ homeostasis [delayed Ca2+ deregulation (DCD)] in rat cerebellar granule cells resulting from chronic activation of NMDA receptors, their role in AMPA/KA-induced DCD remains to be established. The mitochondrial ATP synthase inhibitor oligomycin protected cells against KA- but not NMDA-evoked DCD. In contrast to NMDA-evoked DCD, no additional protection was afforded by the further addition of rotenone. The effects of KA on cytoplasmic Ca2+ homeostasis, including the protection afforded by oligomycin, could be reproduced by veratridine. KA exposure induced a partial mitochondrial depolarization that was enhanced by oligomycin, indicating ATP synthase reversal. The nonglycolytic substrates pyruvate and lactate were unable to maintain Ca2+ homeostasis in the presence of KA. In contrast to NMDA, KA exposure did not cause mitochondrial Ca2+ loading. The data indicate that Na+ entry via noninactivating AMPA/KA receptors or voltage-activated Na+ channels compromises mitochondrial function sufficiently to cause ATP synthase reversal. Oligomycin may protect by preventing the consequent mitochondrial drain of cytoplasmic ATP.