Context-Dependent Modulation of Astrocytic Ca ²⁺ Signals by Mitochondria - A Computational Study

Mitochondria are one of the major regulators of intracellular Ca ²⁺ in the cells, uptaking this ion through the mitochondrial Ca ²⁺ uniporter (MCU) and releasing by the mitochondrial permeability transition pore (mPTP). Astrocytes respond to neurotransmitters and other stimuli by increasing the intracellular Ca ²⁺ concentration, a process called ²⁺ signaling. However, it is not clear how mitochondria interact with the neurotransmitter-triggered Ca ²⁺ responses in astrocytes. To explore this mechanisms, we expanded a previous compartmental model of astrocytes developed by our group including the mitochondrial MCU and mPTP mechanisms controlling the Ca ²⁺ response. We simulate glutamatergic and dopaminergic inputs, modeled as Poisson processes, that promote the synthesis of IP ₃ through the PLC pathway. Here, we used a unipolar and a bifurcated-terminal morphology models and, with exception for the distal compartments, every other compartment have mitochondria. Simulations revealed that mitochondria modulate the Ca ²⁺ response in a context-dependent manner. For weak glutamatergic input, they reduce the frequency of Ca ²⁺ oscillations and the distance these signals propagate from the terminal regions. However, for strong glutamatergic input and in the presence of dopamine, mitochondria enhance the Ca ²⁺ response by reducing the Ca ²⁺ -dependent IP ₃ degradation. Our findings provide computational evidence that mitochondria have a critical role in shaping the spatial organization of Ca ²⁺ singling in astrocytes.