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, mi-tochondrial 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 composi-tion, highlighting its impact on astrocytic homeostasis.

Automated summary

Astrocytes are diverse macroglial cells with various functions and morphologies, containing different types of mitochondria that play important roles in local metabolism and Ca2+ signaling. Ca2+ is crucial for central nervous system processes, and the mitochondrial Ca2+ handling system, including the MCUc, NCLX, and mtPTP, is essential for brain homeostasis and various physiological and pathological processes. This review discusses the molecular composition of the mitochondrial Ca2+ handling system and its impact on astrocytic homeostasis.