ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons
Yusuke Hirabayashi1,2,3,4, Seok-Kyu Kwon1,2,3, Hunki Paek1,2,3, Wolfgang M. Pernice5, Maëla A. Paul1,2,3, Jinoh Lee1,2,3, Parsa Erfani1,2,3, Ashleigh Raczkowski7, Liza A. Pon5 and Franck Polleux1,2,3 * 1Department of Neuroscience, Columbia University; 2Zuckerman Mind Brain Behavior Institute 3Kavli Institute for Brain Science; 4JST; 5Department of Pathology and Cell Biology, Columbia University; 6Simons Electron Microscopy Center, NYSBC
A network of contact sites between the membranes of different organelles are emerging as critical platforms for various forms of intracellular signaling. The interface between ER and mitochondria is of particular interest as a signaling hub because it is thought to play critical physiological functions such as regulation of Ca2+ homeostasis, lipid biogenesis and mitochondrial fission. In addition, changes in the number of these contacts have been reported in various mouse models of neurodegeneration and/or in the brains of patients presenting with various neurodegenerative diseases. However, despite the fact that multiple proteins are enriched at ER-mitochondria contacts sites, the molecular mechanisms underlying ER-mitochondria tethering are still largely unknown in metazoans. Here, we will report the identification of PDZD8 as a novel protein required for ER-mitochondria tethering protein (Hirabayashi et al. Science 2017). Pdzd8 is an integral ER proteins present at ER-mitochondria contact sites. Using 3D FIB-serial EM reconstructions, we demonstrate that PDZD8 is required for the formation of ER-mitochondria contacts in mammalian cells. Using a series of functional loss-of-function and rescue experiments, we found that PDZD8-dependent ER-mitochondria contacts are required for proper Ca2+ exchange between ER and mitochondria in mammalian cells. In dendrites of cortical pyramidal neurons, PDZD8 is required for Ca2+ uptake by mitochondria following synaptically-induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein, which is involved in the regulation of dendritic Ca2+ dynamicsin mammalian neurons.
This work was supported by grants awarded from the NIH (NS089456) (FP), (GM122589 and GM45735) (LP), an award from the Fondation Roger De Spoelberch (FP), International Research Fellowship of the JSPS (YH), and JST/PRESTO (JPMJPR16F7) (YH).
Credits: None available.
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