Deciphering the postsynaptic calcium-mediated energy homeostasis through mitochondria-endoplasmic reticulum contact sites using systems modeling

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, 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 differential distribution of key Ca2+ channels such as IP3 receptor and ryanodine receptor modulate Ca2+ dynamics in response to different stimuli. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the cellular 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

“…Recently, a series of studies on synaptic geometry and structural plasticity have been conducted by us and others [4,3,26,8]. 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 [14,25,44]. 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.…”

Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling

“…Intracellular calcium is a critical cellular second messenger that is closely linked to the induction of synaptic plasticity [42]. In this model, we source reactions established in legacy literature models of neuronal calcium [1–3,38,43]. Calcium influx is initiated by glutamate binding to receptors on the PSD described in receptor models.…”

“…In this work, we use computational modeling to explore how the calcium-AMPK-mTOR signaling axis could couple neuronal energy states and mTOR activity. Computational modeling has vastly contributed to our understanding of neuronal signaling and synaptic plasticity [1][2][3][4][37][38][39]. However, very few of these models feature the importance of metabolic feedback mechanisms known to be critical in synaptic formation and activity.…”