ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons

Science. 2017 Nov 3;358(6363):623-630. doi: 10.1126/science.aan6009.

Yusuke Hirabayashi ¹ ² ³ ⁴, Seok-Kyu Kwon ¹ ² ³, Hunki Paek ¹ ² ³, Wolfgang M Pernice ⁵, Maëla A Paul ¹ ² ³, Jinoh Lee ¹ ² ³, Parsa Erfani ¹ ² ³, Ashleigh Raczkowski ⁶, Donald S Petrey ⁷ ⁸, Liza A Pon ⁵ ⁹, Franck Polleux ¹⁰ ² ³

Affiliations

1 Department of Neuroscience, Columbia University Medical Center, Columbia University, New York, NY 10027, USA.
2 Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
3 Kavli Institute for Brain Science, Columbia University, New York, NY 10027, USA.
4 Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan.
5 Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
6 Simons Electron Microscopy Center, New York Structural Biology Center (NYSBC), New York, NY 10027, USA.
7 Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, NY 10032, USA.
8 Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
9 Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
10 Department of Neuroscience, Columbia University Medical Center, Columbia University, New York, NY 10027, USA. fp2304@cumc.columbia.edu.

PMID: 29097544 DOI: 10.1126/science.aan6009

Abstract

Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)-mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1. PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells. In neurons, PDZD8 was required for calcium ion (CA²⁺) uptake by mitochondria after synaptically induced CA²⁺-release from ER and thereby regulated cytoplasmic CA²⁺ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein in metazoans. We suggest that ER-mitochondria coupling is involved in the regulation of dendritic CA²⁺ dynamics in mammalian neurons.

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