# Role of ER-mitochondria contacts in dendritic Ca2+ homeostasis, synaptic integration and circuit function

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $560,180

## Abstract

Organelle contacts are emerging as critical signaling platforms in metazoan cells. In non-neuronal cells,
many of the important physiological functions played by mitochondria such as Ca2+ uptake and lipid
biogenesis require a specialized structural and functional interface with the smooth endoplasmic reticulum
(ER). Recent data from non-neuronal cells support a model whereby mitochondrial Ca2+ uptake can only
occur upon Ryanodine and/or IP3 receptors-mediated Ca2+ release from the ER at sites of ER-mitochondria
contacts, where Ca2+ transiently reaches high enough concentrations to open the mitochondrial calcium
uniporter (MCU). Therefore, 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. However the pathophysiological impact of these changes in
ER-mitochondria contacts is largely unknown.
The goal of this proposal is to explore 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. Overall, our project will
test, with unprecedented relevance, the role of a new biological interface, ER-mitochondria
contacts, in dendritic Ca2+ dynamics, synaptic integration and circuit function in vivo.

## Key facts

- **NIH application ID:** 9926321
- **Project number:** 5R01NS107483-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** FRANCK POLLEUX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $560,180
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926321

## Citation

> US National Institutes of Health, RePORTER application 9926321, Role of ER-mitochondria contacts in dendritic Ca2+ homeostasis, synaptic integration and circuit function (5R01NS107483-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9926321. Licensed CC0.

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