In the last 5 years, most of the molecules that control mitochondrial Ca²⁺ homeostasis have been finally identified. Mitochondrial Ca²⁺ uptake is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, a macromolecular structure that guarantees Ca²⁺ accumulation inside mitochondrial matrix upon increases in cytosolic Ca²⁺. Conversely, Ca²⁺ release is under the control of the Na⁺/Ca²⁺ exchanger, encoded by the NCLX gene, and of a H⁺/Ca²⁺ antiporter, whose identity is still debated. The low affinity of the MCU complex, coupled to the activity of the efflux systems, protects cells from continuous futile cycles of Ca²⁺ across the inner mitochondrial membrane and consequent massive energy dissipation. In this review, we discuss the basic principles that govern mitochondrial Ca²⁺ homeostasis and the methods used to investigate the dynamics of Ca²⁺ concentration within the organelles. We discuss the functional and structural role of the different molecules involved in mitochondrial Ca²⁺ handling and their pathophysiological role.

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