Abstract

Calcium spikes established by IP₃ receptor-mediated Ca²⁺ release from the endoplasmic reticulum (ER) are transmitted effectively to the mitochondria, utilizing local Ca²⁺ interactions between closely associated subdomains of the ER and mitochondria. Since the outer mitochondrial membrane (OMM) has been thought to be freely permeable to Ca²⁺, investigations have focused on IP₃-driven Ca²⁺ transport through the inner mitochondrial membrane (IMM). Here we demonstrate that selective permeabilization of the OMM by tcBid, a proapoptotic protein, results in an increase in the magnitude of the IP₃-induced mitochondrial [Ca²⁺] signal. This effect of tcBid was due to promotion of activation of Ca²⁺ uptake sites in the IMM and, in turn, to facilitation of mitochondrial Ca²⁺ uptake. In contrast, tcBid failed to control the delivery of sustained and global Ca²⁺ signals to the mitochondria. Thus, our data support a novel model that Ca²⁺ permeability of the OMM at the ER– mitochondrial interface is an important determinant of local Ca²⁺ signalling. Facilitation of Ca²⁺ delivery to the mitochondria by tcBid may also support recruitment of mitochondria to the cell death machinery.