tcBid promotes Ca2+ signal propagation to the mitochondria: control of Ca2+ permeation through the outer mitochondrial membrane

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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.