Ca²⁺ Fluxes across Membrane Contact Sites

The calcium ion (Ca²⁺) is a pivotal second messenger orchestrating diverse cellular functions, including metabolism, signaling, and apoptosis. Membrane contact sites (MCSs) are critical hubs for Ca²⁺ exchange, enabling rapid and localized signaling across cell compartments. Well-characterized interfaces, such as those between the endoplasmic reticulum (ER) and mitochondria and ER-plasma membrane (PM), mediate Ca²⁺ flux through specialized channels. Less understood, yet significant, contacts involving Golgi, lysosomes, peroxisomes, and the nucleus further expand the landscape of intracellular Ca²⁺ signaling. These organelles are engaged in Ca²⁺ homeostasis mainly through their MCS, but the molecular players and the mechanisms regulating the process of Ca²⁺ transfer remain incompletely elucidated. This review provides a comprehensive overview of Ca²⁺ signaling across diverse MCS, emphasizing understudied organelles and the need for further investigation to uncover novel therapeutic opportunities.