The regulation of neuronal mitochondrial metabolism by calcium

Abstract

Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca2+ acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca2+ stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca2+-regulated mitochondrial carriers, whereas an increase in matrix Ca2+ stimulates the citric acid cycle and ATP synthase. The aspartate-glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate-aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca2+ and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K+-depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca2+ influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca2+]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca2+ signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca2+ is increased and mitochondria fragmented. Thus, the fine tuning of Ca2+ signals plays a key role in shaping mitochondrial bioenergetics.