Lucia Barazzuol1, Marisa Brini2,3 and Tito Calì1,3,4 1Department of Biomedical Sciences (DSB), University of Padova, Padova 35131, Italy 2Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy 3Study Center for Neurodegeneration (CESNE); and University of Padova, Padova 35131, Italy 4Padova Neuroscience Center (PNC), University of Padova, Padova 35131, Italy Correspondence: tito.caliunipd.it

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.