Regulation of neuronal energy metabolism by calcium: Role of MCU and Aralar/malate-aspartate shuttle

Calcium is a major regulator of cellular metabolism. Calcium controls mitochondrial respiration, and calcium signaling is used to meet cellular energetic demands through energy production in the organelle. Although it has been widely assumed that Ca²⁺-actions require its uptake by mitochondrial calcium uniporter (MCU), alternative pathways modulated by cytosolic Ca²⁺ have been recently proposed. Recent findings have indicated a role for cytosolic Ca²⁺ signals acting on mitochondrial NADH shuttles in the control of cellular metabolism in neurons using glucose as fuel. It has been demonstrated that AGC1/Aralar, the component of the malate/aspartate shuttle (MAS) regulated by cytosolic Ca²⁺, participates in the maintenance of basal respiration exerted through Ca²⁺-fluxes between ER and mitochondria, whereas mitochondrial Ca²⁺-uptake by MCU does not contribute. Aralar/MAS pathway, activated by small cytosolic Ca²⁺ signals, provides in fact substrates, redox equivalents and pyruvate, fueling respiration. Upon activation and increases in workload, neurons upregulate OxPhos, cytosolic pyruvate production and glycolysis, together with glucose uptake, in a Ca²⁺-dependent way, and part of this upregulation is via Ca²⁺ signaling. Both MCU and Aralar/MAS contribute to OxPhos upregulation, Aralar/MAS playing a major role, especially at small and submaximal workloads. Ca²⁺ activation of Aralar/MAS, by increasing cytosolic NAD⁺/NADH provides Ca²⁺-dependent increases in glycolysis and cytosolic pyruvate production priming respiration as a feed-forward mechanism in response to workload. Thus, except for glucose uptake, these processes are dependent on Aralar/MAS, whereas MCU is the relevant target for Ca²⁺ signaling when MAS is bypassed, by using pyruvate or β-hydroxybutyrate as substrates.