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. [email protected].
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.