(28) LOCAL CALCIUM CONTROL BETWEEN IP3 RECEPTORS AND MITOCHONDRIA

Gyorgy Hajnoczky, Gyorgy Csordas and Andrew P. Thomas
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107

Transmission of cytosolic [Ca2+] ([Ca2+]c) oscillations into the mitochondrial matrix is thought to be supported by local calcium control between IP3 receptor Ca2+ channels (IP3R) and mitochondria but it has been difficult to study the coupling mechanisms. We established a permeabilized cell model in which the Ca2+ coupling between endoplasmic reticulum (ER) and mitochondria is retained and mitochondrial [Ca2+] ([Ca2+]m) can be monitored fluorometrically. We demonstrate that maximal activation of mitochondrial Ca2+ uptake is evoked by IP3-induced perimitochondrial [Ca2+] elevations, which appear to reach values >20-fold higher than the global increases of [Ca2+]c. When incremental doses of IP3 were added [Ca2+]m elevations followed the quantal pattern of Ca2+ mobilization even at the level of individual mitochondria, but suboptimal or gradual increases of IP3 evoked relatively small [Ca2+]m responses. We conclude that each mitochondrial Ca2+ uptake site faces multiple IP3R, a concurrent activation of which is required for optimal activation of mitochondrial Ca2+ uptake. This architecture explains why calcium oscillations evoked by synchronized periodic activation of IP3R, are particularly effective to establish dynamic control over mitochondrial metabolism.