Mitochondrial Ca2+ uptake depends on the spatial and temporal profile of cytosolic Ca2+ signals

Collins, Tony J.; Lipp, Peter; Berridge, Michael J. and Bootman, Martin D. (2001). Mitochondrial Ca2+ uptake depends on the spatial and temporal profile of cytosolic Ca2+ signals. Journal of Biological Chemistry, 276(28) pp. 26411–26420.




Using confocal imaging of Rhod-2-loaded HeLa cells, we examined the ability of mitochondria to sequester Ca2+ signals arising from different sources. Mitochondrial Ca2+ (Ca2+mit) uptake was stimulated by inositol 1,4,5-trisphosphate (InsP3)-evoked Ca2+ release, capacitative Ca2+ entry, and Ca2+ leaking from the endoplasmic reticulum. For each Ca2+ source, the relationship between cytosolic Ca2+ (Ca2+cyt) concentration and Ca2+mit was complex. With Ca2+cyt < 300 nM, a slow and persistent Ca2+mit uptake was observed. If Ca2+cyt increased above ~ 400 nM, Ca2+mit uptake accelerated sharply. For equivalent Ca2+cyt increases, the rate of Ca2+mit rise was greater with InsP3-evoked Ca2+ signals than any other source. Spatial variation of the Ca2+mit response was observed within individual cells. Both the fraction of responsive mitochondria and the amplitude of the Ca2+mit response were graded in direct proportion to stimulus concentration. Trains of repetitive Ca2+ oscillations did not maintain elevated Ca2+mit levels. Only low frequency Ca2+ transients (<1/15 min) evoked repetitive Ca2+mit signals. Our data indicate that there is a lag between Ca2+cyt and Ca2+mit increases but that mitochondria will accumulate calcium when it is elevated over basal levels regardless of its source. Furthermore, in addition to the characteristics of Ca2+ signals, Ca2+ uniporter desensitization and proximity of mitochondria to InsP3 receptors modulate mitochondrial Ca2+ responses.

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