Enjoy the Trip: Calcium in Mitochondria Back and Forth

In the last 5 years, most of the molecules that control mitochondrial Ca 2+ homeostasis have been finally identified. Mitochondrial Ca 2+ uptake is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, a macromolecular structure that guarantees Ca 2+ accumulation inside mitochondrial matrix upon increases in cytosolic Ca 2+ . Conversely, Ca 2+ release is under the control of the Na + Ca 2+ exchanger, encoded by the NCLX gene, and of a H + Ca 2+ 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 Ca 2+ across the inner mitochondrial membrane and consequent massive energy dissipation. In this review, we discuss the basic principles that govern mitochondrial Ca 2+ homeostasis and the methods used to investigate the dynamics of Ca 2+ concentration within the organelles. We discuss the functional and structural role of the different molecules involved in mitochondrial Ca 2+ handling and their pathophysiological role.