Mitochondria rapidly accumulate Ca²⁺ through a low-affinity uptake system (the mitochondrial Ca²⁺ uniporter, MCU) because they are exposed to high [Ca²⁺] microdomains generated by the opening of ER Ca²⁺ channels. These rapid [Ca²⁺] changes stimulate Ca²⁺-sensitive dehydrogenases of the mitochondrial matrix, and hence rapidly upregulate ATP production in stimulated cells. Ca²⁺ also sensitizes to cell death mediators, e.g. ceramide. Accordingly, we demonstrated that Bcl-2 reduces the state of filling of ER Ca²⁺ stores, and this alteration is effective in reducing the sensitivity to apoptotic challenges. I discuss two topics. The first is the current understanding of the link between calcium dysregulation in mitochondria and cell death, with special focus on neuromuscular diseases. The second topic is our recent discovery of the molecular identity of the MCU, i.e. the key molecule of mitochondrial Ca²⁺ homeostasis. I will present the strategy, and the experiments, that allowed to identify the protein, that remained elusive for 50 years. Then, I will present data that clarify the composition and the regulatory mechanisms of this highly sophisticated signaling machinery. Finally, I will that molecular targeting of MCU allowed novel insight into the regulation of cellular metabolism and cell death processes.

References D. De Stefani, A. Raffaello, E. Teardo, I. Szabo, R. Rizzuto (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336-340