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 IP₃ receptor Ca²⁺ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca²⁺ 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 Ca²⁺ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca²⁺ 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 Ca²⁺ transfer without changing ER Ca²⁺ release, despite attenuating mitochondrial Ca²⁺ 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 Ca²⁺ signal propagation into the mitochondria.