Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism

Abstract

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP₃ receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca²⁺ coupling, IP3Rs captured at mitochondria promptly mediate Ca²⁺ transfer, stimulating mitochondrial oxidative metabolism. The Ca²⁺ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when ‘parked’, mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.

The formation and dissolution of ER-Mitochondria contacts is unclear. Here, authors show that the IP3 receptor traffics in and out of the contacts and, when trapped, improves calcium signaling to stimulate energy metabolism.