Final Report Summary - MITOCALCIUM (Mitochondrial calcium signalling: molecules, roles and pharmacological targeting)
Cell to cell communication requires rapid changes in the intracellular concentration of calcium (Ca2+) that generate the so-called Ca2+ signals. Ca2+ ions cross the membranes through channels, exchangers and pumps and the delicate equilibrium among these components allows every cell to respond to a variety of stimuli and activate specific cellular outcome (e.g. gene transcription, secretion, contraction, etc.). In addition, this versatility is also guaranteed by the fine compartmentalization of Ca2+ signals. Mitochondria are small specialized intracellular compartment present in almost every cell type. Their primary function is to produce energy for the whole cell in the form of a small molecule called ATP, which represent the common fuel for all cellular reactions. The accumulation of Ca2+ inside mitochondria is a signal necessary to sustain energy production. However, too much Ca2+ inside mitochondria (a condition known as “mitochondrial Ca2+ overload”) can also lead to cell death. Therefore, understanding how Ca2+ flows in and out of mitochondria is a fundamental aspect of cell biology with broad implications for many human pathologies. The mitoCalcium project originated from the discovery by our group of the channel that allows Ca2+ to enter inside mitochondria (named Mitochondrial Calcium Uniporter, MCU). The proposal was aimed to understand how this channel works and its contribution to organism physiopathology. We used a multidisciplinary approach and demonstrated that MCU is part of a complex macromolecular structure, named MCU complex, that tightly controls Ca2+ accumulation inside mitochondria. We thus identified and characterized several genes and proteins whose function was completely unknown five years ago. Overall, our understanding of the molecular machinery controlling mitochondrial Ca2+ uptake has astonishingly improved thanks to the mitoCalcium project. We now know the proteins that form the Ca2+-selective pore within the membrane, the mechanism controlling the opening and closure of the channel, as well as the composition of this complex in different tissues. In addition, we contributed to the elucidation of the role of mitochondrial Ca2+ accumulation in physiology and pathology. In particular, we focused on the role of MCU in skeletal muscle and demonstrated that enhancing mitochondrial Ca2+ uptake in this tissue can prevent the loss of muscle mass. Finally, we also identified a panel of small molecules that can either increase or decrease mitochondrial Ca2+ uptake, thus leading the way to develop novel pharmacological strategies with a significant therapeutic potential.