Research Article

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

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Science  03 Nov 2017:
Vol. 358, Issue 6363, pp. 623-630
DOI: 10.1126/science.aan6009

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Making the right contacts

Contacts between the endoplasmic reticulum (ER) and mitochondria mediate key physiological processes such as Ca2+ exchange and lipid biogenesis. In yeast, ER and mitochondria are tethered by a complex of four proteins called ERMES. However, no functional orthologs of these ERMES complex proteins have been identified in metazoans. Hirabayashi et al. identified PDZD8 as a structural and functional ortholog of the yeast ERMES protein MMM1 (see the Perspective by Lombardi and Elrod). PDZD8 was found at ER-mitochondria contact sites and was required for ER-mitochondria tethering in mammalian cells. In neuronal dendrites, PDZD8 regulated synaptically evoked Ca2+ dynamics, which underscores the importance of interorganelle membrane contacts in cell physiology.

Science, this issue p. 623; see also p. 591

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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