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

Abstract Mitochondria regulate intracellular Ca 2+ by uptake through the mitochondrial Ca 2+ uniporter (MCU) and release via the mitochondrial permeability transition pore (mPTP). In astrocytes, neurotransmitter stimulation evokes Ca 2+ 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 IP 3 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 Ca 2+ 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 Ca 2+ responses by reducing Ca 2+ -dependent IP 3 degradation. These results suggest that mitochondria can play an important role in shaping the spatial organization of Ca 2+ signaling in astrocytes.