The Mitochondrial Calcium Uniporter: From Parts to Signaling Networks

Mitochondria act as dynamic signaling hubs, constantly adapting to tissue-specific metabolic demands to ensure cell homeostasis. Central to this role is their capacity to take up calcium (Ca²⁺) into the matrix, a process that regulates energy production, cell death pathways, and broader cellular signaling. For decades, mitochondrial Ca²⁺ (mt-Ca²⁺) uptake was firmly established at the physiological level, yet the identity of the proteins involved remained elusive. The breakthrough discovery of the mitochondrial calcium uniporter complex (MCUC) has finally enabled genetic dissection of mt-Ca²⁺ fluxes and revealed its pivotal role in health and disease. Here, we retrace the trajectory of the field from the pioneering observations of the 1960s to the molecular era of the MCUC, emphasizing the latest advances in its regulation, integration into cellular networks, and pharmacological targeting.