Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

A Leung,P Rangamani,D Ohadi,G Pekkurnaz

doi:10.1038/s41540-021-00185-7

A Leung, P Rangamani + Show 2 more

Open Access

https://doi.org/10.1038/s41540-021-00185-7

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Abstract

Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria (MERCs), which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics.We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.

Highlights

Compartmentalized calcium handling in postsynaptic structures underlies synaptic communication and controls synaptic plasticity, which is the bidirectional modulation of synaptic strength that is thought to underlie learning and memory formation[1]
We found that the mitochondria ER Contact region (MERC) leads to a significant increase in mitochondrial calcium, and subsequently Adenine triphosphate (ATP) production
We constructed a spatial model with five compartments: the postsynaptic density (PSD), the cytosol, one mitochondria, the endoplasmic reticulum (ER), and a mitochondria ER Contact region (MERC) (Fig. 1a, b)

Summary

Introduction

Compartmentalized calcium handling in postsynaptic structures underlies synaptic communication and controls synaptic plasticity, which is the bidirectional modulation of synaptic strength that is thought to underlie learning and memory formation[1]. In excitatory neurons during synaptic transmission, glutamate released from the presynaptic bouton leads to a localized increase in calcium at the postsynaptic dendrite that is critical for the induction of synaptic plasticity[2,3]. Small bulbous protrusions called dendritic spines act as biochemical computation units that regulate the duration and spread of postsynaptic calcium fluxes produced by glutamatergic neurotransmission[4]. The temporal dynamics of calcium, and the coupling to downstream signaling pathways in dendritic spines depend on many factors, including the nature of stimulus as well as the positioning of the calcium storage organelles, the endoplasmic reticulum (ER), and the mitochondria[5,6]. The intimate contact between mitochondria and ER along dendrites allows for a functional interorganellar coupling and plays a central role in the regulation of the postsynaptic calcium dynamics (Fig. 1a).

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