Context-Dependent Modulation of Astrocytic Ca2+ Signals by Mitochondria - A Computational Study

Abstract

Mitochondria are one of the major regulators of intracellular Ca2+ in the cells, uptaking this ion through the mitochondrial Ca2+ uniporter (MCU) and releasing by the mitochondrial permeability transition pore (mPTP). Astrocytes respond to neurotransmitters and other stimuli by increasing the intracellular Ca2+ concentration, a process called 2+ signaling. However, it is not clear how mitochondria interact with the neurotransmitter-triggered Ca2+ 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 Ca2+ response. We simulate glutamatergic and dopaminergic inputs, modeled as Poisson processes, that promote the synthesis of IP3 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 Ca2+ response in a context-dependent manner. For weak glutamatergic input, they reduce the frequency of Ca2+ 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 Ca2+ response by reducing the Ca2+-dependent IP3 degradation. Our findings provide computational evidence that mitochondria have a critical role in shaping the spatial organization of Ca2+ singling in astrocytes.