Enjoy the Trip: Calcium in Mitochondria Back and Forth

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.