Context-Dependent modulation of astrocytic Ca²⁺ signals by mitochondria: a computational study

Mitochondria regulate intracellular Ca²⁺ by uptake through the mitochondrial Ca²⁺ uniporter (MCU) and release via the mitochondrial permeability transition pore (mPTP). In astrocytes, neurotransmitter stimulation evokes Ca²⁺ signaling, yet the role of mitochondria in shaping these responses remains unclear. We extended a compartmental astrocyte model developed by our group to include MCU- and mPTP-mediated dynamics, and simulated glutamatergic and dopaminergic inputs modeled as Poisson processes driving IP₃ synthesis through the phospholipase-C (PLC) pathway. Both unipolar and bifurcated-terminal morphologies were considered, with mitochondria positioned in alternating compartments starting from the soma; distal compartments contained mitochondria only when sufficiently large. Simulations show that mitochondria modulate Ca²⁺ signaling in a context-dependent manner: under weak glutamatergic input, they reduce oscillation frequency and limit signal propagation, whereas under strong glutamatergic input or dopaminergic modulation, they enhance Ca²⁺ responses by reducing Ca²⁺-dependent IP₃ degradation. These results suggest that mitochondria can play an important role in shaping the spatial organization of Ca²⁺ signaling in astrocytes.