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

Katona, Máté and Bartók, Ádám and Nichtova, Zuzana and Csordás, György and Berezhnaya, Elena and Weaver, David and Ghosh, Arijita and Várnai, Péter and Yule, David I. and Hajnóczky, György (2022) Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism. NATURE COMMUNICATIONS, 13 (1). No. 6779. ISSN 2041-1723

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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 IP 3 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 Ca 2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca 2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca 2+ 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.

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