The MCU complex in cell death.

During the 60s, the notion that positively charged Ca ions are rapidly accumulated in energized mitochondria has been first established. In the following decades, mitochondrial Ca homeostasis was shown to control cell metabolism, cell survival and other cell-specific functions through different mechanism. However, the molecular identity of the molecules controlling this process remained a mystery until just few years ago, when both mitochondrial Ca uptake and release systems were genetically dissected. This finally opened the possibility to develop genetic model to directly test the contribution of mitochondrial Ca homeostasis to cellular functions. Although the picture is still far from being clear, we here summarize and critically evaluate the current knowledge on how mitochondrial Ca handling controls cell death.