The ability of mitochondria to take up Ca
2+ has important functional implications for modulation of cellular Ca
2+ signaling. Mitochondrial Ca
2+ uptake is stimulated by an increase in cytosolic Ca
2+ concentration ([Ca
2+]
c). Here, we found that the increase in mitochondrial Ca
2+ concentration ([Ca
2+]
m) occurs in two steps in a single antigen-activated mast cell in the presence of extracellular Ca
2+ (1.0 m
M). The two-step elevation of [Ca
2+]
m was also observed after adding thapsigargin, an inhibitor of sarcoplasmic/endoplasmic reticulum Ca
2+-ATPase. The proportion of mitochondria showing the two-step Ca
2+ elevation dropped off in direct accord with decrease in extracellular Ca
2+ concentration. The second step of the [Ca
2+]
m increase was suppressed significantly in the absence of extracellular Ca
2+ and in knockdown cells of stromal interaction molecule 1 (STIM1), an essential molecule on endoplasmic reticulum (ER) membrane for store-operated Ca
2+ entry, in the presence of extracellular Ca
2+ (1.0 m
M), while the first elevation was not affected in either case. The results indicate that mitochondria take up cytosolic Ca
2+ in two steps; first and second uptakes are derived from the Ca
2+ release from ER and the Ca
2+ influx through store-operated Ca
2+ channels, respectively. Additionally, rotenone and antimycin A, which are inhibitors of mitochondrial electron transport complex I and III, respectively, diminished mitochondrial Ca
2+ uptake and significantly suppressed degranulation stimulated with antigen. The mitochondrial Ca
2+ uptake may modulate mast cell function by regulating the [Ca
2+]
c.
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