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

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.

Morphological principles of neuronal mitochondria

“…Parallel studies have focused on the role of the ER and mitochondria in regulating the spine calcium and how internal organelles can alter the calcium and ATP dynamics (Garcia et al, 2019;Leung et al, 2021;Singh et al, 2021). We anticipate that the mitochondrial geometry features we describe here will now serve as a platform for future high-dimensional simulations of mitochondrial dynamics and quantitative mapping of the mitochondrial structure-neuronal energy landscape.…”

GPCR/endocytosis/ERK signaling/S2R is involved in the regulation of the internalization, mitochondria-targeting and -activating properties of human salivary histatin 1

“…This result suggests that Hst1 enhances the formation of MERCs, thereby promoting mitochondrial energy metabolism. 56 …”

Mitochondria-Endoplasmic Reticulum Interaction in Central Neurons

“…Mitochondrial clusters occupy most of the dendritic branches and are closely associated with the ER, especially at the base of the spines (Figure 1) [18]. However, such a distribution of ER and mitochondria is not constant.…”

“…Calcium deposition in the postsynaptic terminal underlies synaptic transmission, driving a wide range of synaptic plasticity mechanisms for efficient learning and memory processing. Excitatory or inhibitory inputs lead to a differentiated local increase of calcium in dendritic spines, which functions as units of biophysical and biochemical computations in the neuron, regulating their duration and distribution [18]. The volume of the SA, also considered an ER store, affects the temporal dynamics of Ca 2+ , its distribution to neighboring dendrite sites, and binding to numerous Ca 2+ − gated signaling pathways [2].…”