Intermembrane Coupling Between Bcl-xL and the IP3 Receptor Supports Local Ca2+ Transfer at ER-Mitochondrial Contacts

Authors

• Arijita Ghosh, Thomas Jefferson UniversityFollow
• David Weaver, Thomas Jefferson UniversityFollow
• Chi Li
• György Hajnóczky, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

7-30-2026

Comments

This article is the author's final published version in Cell Reports, Volume 45, Issue 8, August 25, 2026, Article number 117767. 

The published version is available at https://doi.org/10.1016/j.celrep.2026.117767. Copyright © 2026 The Author(s). Published by Elsevier Inc.

Abstract

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. © 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/

Recommended Citation

Ghosh, Arijita; Weaver, David; Li, Chi; and Hajnóczky, György, "Intermembrane Coupling Between Bcl-xL and the IP3 Receptor Supports Local Ca2+ Transfer at ER-Mitochondrial Contacts" (2026). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 501.
https://jdc.jefferson.edu/pacbfp/501

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

42531130

Language

English