After half a century mitochondrial calcium in‐ and efflux machineries reveal themselves

Mitochondrial Ca 2+ uptake and release play a fundamental role in the control of different physiological processes, such as cytoplasmic Ca 2+ signalling, ATP production and hormone metabolism, while dysregulation of mitochondrial Ca 2+ handling triggers the cascade of events that lead to cell death. The basic mechanisms of mitochondrial Ca 2+ homeostasis have been firmly established for decades, but the molecular identities of the channels and transporters responsible for Ca 2+ uptake and release have remained mysterious until very recently. Here, we briefly review the main findings that have led to our present understanding of mitochondrial Ca 2+ homeostasis and its integration in cell physiology. We will then discuss the recent work that has unravelled the biochemical identity of three key molecules: NCLX, the mitochondrial Na + /Ca 2+ antiporter, MCU, the pore‐forming subunit of the mitochondrial Ca 2+ uptake channel, and MICU1, one of its regulatory subunits.