Mitochondrial Calcium Transport in Amino Acid Metabolism: From nutritional responses to metabolic regulation

Mitochondrial calcium (Ca ²⁺ ) transport is a central regulator of cellular metabolism, linking bioenergetics, signaling, and organelle function. While its role in controlling oxidative phosphorylation and cell fate is well established, emerging evidence indicates that mitochondrial Ca ²⁺ handling is also tightly connected to amino acid metabolism and nitrogen balance. In this review, we integrate classical and recent findings to examine how mitochondrial Ca ²⁺ transporters, including the mitochondrial calcium uniporter complex (MCUc), Na ⁺ /Ca ²⁺ exchangers, and H ⁺ /Ca ²⁺ exchange systems, respond to nutritional cues and contribute to metabolic adaptation. We discuss how variations in amino acid availability and dietary protein intake may modulate the expression and activity of Ca ²⁺ transport machinery, and explore the emerging role of mitochondrial proteases in regulating transporter turnover and activity, highlighting unexplored questions and future prospects in the field. We discuss how mitochondrial Ca ²⁺ fluxes influence amino acid-sensitive processes including autophagy, mitochondrial morphology, and substrate utilization, while also potentially modulating the urea cycle through effects on key enzymes and metabolite transporters. Overall, we find that mitochondrial Ca ²⁺ transport is a dynamic interface between nutrient availability and metabolic regulation, with implications for physiology and metabolic disease, but significant gaps remain regarding specific mechanisms within the integration of Ca ²⁺ signaling with amino acid-sensing pathways.