Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria

Transmission of cytosolic [Ca2+] ([Ca2+](c)) oscillations into the mitochon drial matrix is thought to be supported by local calcium control between IP 3 receptor Ca2+ channels (IP3R) and mitochondria, but study of the coupling mechanisms has been difficult. We established a permeabilized cell model i n which the Ca2+ coupling between endoplasmic reticulum (ER) and mitochondr ia is retained, and mitochondrial [Ca2+] ([Ca2+](m)) can be monitored by fl uorescence imaging. 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), Incremental doses of IP3 elicited [Ca2+](m) elevations that follo wed the quantal pattern of Ca2+ mobilization, even at the level of individu al mitochondria, In contrast, gradual increases of IP3 evoked relatively sm all [Ca2+](m) responses despite eliciting similar [Ca2+](c) increases. We c onclude that each mitochondrial Ca2+ uptake site faces multiple IP3R, a con current activation of which is required for optimal activation of mitochond rial Ca2+ uptake. This architecture explains why calcium oscillations evoke d by synchronized periodic activation of IP3R are particularly effective in establishing dynamic control over mitochondrial metabolism. Furthermore, o ur data reveal fundamental functional similarities between ER-mitochondrial Ca2+ coupling and synaptic transmission.