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The relationship between changes in mitochondrial membrane potential (Δψ_m) and the failure of cytoplasmic Ca²⁺ homeostasis, delayed Ca²⁺deregulation (DCD), is investigated for cultured rat cerebellar granule cells exposed to glutamate. To interpret the single-cell fluorescence response of cells loaded with tetramethylrhodamine methyl ester (TMRM⁺) or rhodamine-123, we devised and validated a mathematical simulation with well characterized effectors of Δψ_m and plasma membrane potential (Δψ_P). Glutamate usually caused an immediate decrease in Δψ_m of <10 mV, attributable to Ca²⁺ accumulation rather than enhanced ATP demand, and these cells continued to generate ATP by oxidative phosphorylation until DCD. Cells for which the mitochondria showed a larger initial depolarization deregulated more rapidly. The mitochondria in a subpopulation of glutamate-exposed cells that failed to extrude Ca …