Abstract
Mitochondria within cultured rat cerebellar granule cells have a complex influence on cytoplasmic free Ca
2+
([Ca
2+
]
c
) responses to glutamate. A decreased initial [Ca
2+
]
c
elevation in cells whose mitochondria are depolarized by inhibition of the ATP synthase and respiratory chain (conditions which avoid ATP depletion) was attributed to enhanced Ca
2+
extrusion from the cell rather than inhibited Ca
2+
entry via the NMDA receptor. Even in the presence of elevated extracellular Ca
2+
, when [Ca
2+
]
c
responses were restored to control values, such cells showed resistance to acute excitotoxicity, defined as a delayed cytoplasmic Ca
2+
deregulation (DCD) during glutamate exposure. DCD was a function of the duration of mitochondrial polarization in the presence of glutamate rather than the total period of glutamate exposure. Once initiated, DCD could not be reversed by NMDA receptor inhibition. In the absence of ATP synthase inhibition, respiratory chain inhibitors produced an immediate Ca
2+
deregulation (ICD), ascribed to an ATP deficit. In contrast to DCD, ICD could be reversed by subsequent ATP synthase inhibition with or without additional NMDA receptor blockade. DCD could not be ascribed to the failure of an ATP yielding metabolic pathway. It is concluded that mitochondria can control Ca
2+
extrusion from glutamate-exposed granule cells by the plasma membrane in three ways: by competing with efflux pathways for Ca
2+
, by restricting ATP supply, and by inducing a delayed failure of Ca
2+
extrusion. Inhibitors of the mitochondrial permeability transition only marginally delayed the onset of DCD.