IN Xenopus oocytes, as well as other cells, inositol-1,4,5-trisphosphate (Ins(1,4,5)P-3)-induced Ca2+ release(1-4) is an excitable process that generates propagating Ca2+ waves(5-7) that annihilate upon collision(8-12). The fundamental property responsible for excitability appears to be the Ca2+ dependency of the Ins(1,4,5)P-3 receptor(9). Here we report that Ins(1,4,5)P-3-induced Ca2+ were activity is strengthened by oxidizable substrates that energize mitochrondria, increasing Ca2+ wave amplitude, velocity and interwave period. The effects of pyruvate/malate are blocked by ruthenium red at the Ca2+ uniporter, by rotenone at complex I, and by antimycin A at complex III, and are subsequently rescued at complex IV by ascorbate tetramethylphenylenediamine (TMPD)(14). Our data reveal that potential-driven mitochondrial Ca2+ uptake is a major factor in the regulation of Ins(1,4,5)P-3-induced Ca2+ release and clearly demonstrate a physiological role of mitrochondria in intracellular Ca2+ signalling.