Mitochondrial Ca²⁺ handling as a cell signaling hub: lessons from astrocyte function

Astrocytes are a heterogenous population of macroglial cells spread throughout the central nervous system with diverse functions, expression signatures, and intricate morphologies. Their subcellular compartments contain a distinct range of mitochondria, with functional microdomains exhibiting widespread activities, such as controlling local metabolism and Ca²⁺ signaling. Ca²⁺ is an ion of utmost importance, both physiologically and pathologically, and participates in critical central nervous system processes, including synaptic plasticity, neuron–astrocyte integration, excitotoxicity, and mitochondrial physiology and metabolism. The mitochondrial Ca²⁺ handling system is formed by the mitochondrial Ca²⁺ uniporter complex (MCUc), which mediates Ca²⁺ influx, and the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX), responsible for most mitochondrial Ca²⁺ efflux, as well as additional components, including the mitochondrial permeability transition pore (mtPTP). Over the last decades, mitochondrial Ca²⁺ handling has been shown to be key for brain homeostasis, acting centrally in physiopathological processes such as astrogliosis, astrocyte–neuron activity integration, energy metabolism control, and neurodegeneration. In this review, we discuss the current state of knowledge regarding the mitochondrial Ca²⁺ handling system molecular composition, highlighting its impact on astrocytic homeostasis.