Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts

Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP 3 receptor Ca 2+ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca 2+ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca 2+ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca 2+ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy of ER-mitochondrial Ca 2+ transfer without changing ER Ca 2+ release, despite attenuating mitochondrial Ca 2+ uptake. We find interaction between Bcl-xL and each IP3R isoform occurring at the mitochondria and a complex formed by OMM-localized Bcl-xL and IP3Rs. OMM Bcl-xL interacts with IP3Rs in trans at ER-mitochondrial contacts to optimize local Ca 2+ signal propagation into the mitochondria.