University of Cambridge > > MRC Mitochondrial Biology Unit Seminars > Exploring new roles for ER-mitochondria organelle contacts in neurons

Exploring new roles for ER-mitochondria organelle contacts in neurons

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Interfaces between organelles, such as ER and mitochondria, are emerging as critical platforms for many biological responses in eukaryotic cells. However, the function of ER-mitochondria coupling in developing and adult neurons is currently unknown despite recent ultrastructural evidence (including our own results) showing that numerous direct contacts between ER and mitochondria can be observed in dendrites in vivo. In addition, changes in the extent of ER-mitochondria contacts have been reported in various models of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. To date, the pathophysiological impact of these changes in ER-mitochondria contacts is largely unknown. I will give an update on our project aimed at exploring the role of ER-mitochondria interface in neuronal development, synaptic integration and circuit function. The major roadblock to study the function of ER-mitochondria coupling in any cell types including neurons is due to the absence of a molecular toolkit required to manipulate this organelle interface. We recently identified Pdzd8 as an ER protein playing a critical role in ER-mitochondria tethering (Hirabaryashi et al. Science 2017). We found that in cortical neurons, PDZD8 is required for Ca2+ uptake by mitochondria following synaptically-induced Ca2+release from ER and thereby regulates cytoplasmic Ca2+ dynamics in dendrites. Our results identify PDZD8 as the first, critical ER mitochondria tethering protein in metazoan cells and uncover a novel role for ER-mitochondria coupling in the regulation of dendritic Ca2+ dynamics in mammalian neurons. We hypothesize that PDZD8 -dependent ER-mitochondria tethering plays critical roles in regulating cytoplasmic Ca2+ homeostasis in dendrites and might contribute to the formation of branch-specific Ca2+ ‘domains’ regulating synaptic integration and therefore in the dendritic properties underlying circuit function. We are currently testing the role of ER-mitochondria contact, in dendritic Ca2+ dynamics, synaptic integration and circuit function in vivo

This talk is part of the MRC Mitochondrial Biology Unit Seminars series.

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