Abstract
Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP3 receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts. This role is independent of calcium fluxes. We also show that, while each isoform can support contacts, type 2 IP3R is the most effective in delivering calcium to the mitochondria. Thus, these studies reveal a non-canonical, structural role for the IP3Rs and direct attention towards the type 2 IP3R that was previously neglected in the context of ER-mitochondrial calcium signaling.
Highlights
Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP3 receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival
This phenomenon might be caused by a stronger physical interaction between the ER and mitochondria in the presence of IP3Rs, which keep the ER co-distributed with mitochondria when the cells are polarized by an adhesion surface (Cell-Tak coated coverglass), but Airyscan imaging does not have the resolution to directly visualize
We have examined the properties of the three mammalian IP3Rs in the context of the structural organization and Ca2+ signal transmission between the ER and mitochondria
Summary
Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP3 receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ERmitochondrial contacts This role is independent of calcium fluxes. Direct local [Ca2+] measurements showed the IP3R-mediated Ca2+ release can expose the adjacent mitochondrial surface to 10–30 times larger [Ca2+]cyto than the global [Ca2+]cyto increase[16,17]
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