Balancing ER-Mitochondrial Ca²⁺ Fluxes in Health and Disease

Organelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca²⁺-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca²⁺-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca²⁺ signals from the ER toward mitochondria. This provides tight control of mitochondrial functions at the microdomain level. Here, we discuss how ER–mitochondrial Ca²⁺ transfers support cell function and how their dysregulation underlies, drives, or contributes to pathogenesis and pathophysiology, with a major focus on cancer and neurodegeneration but also with attention to other diseases such as diabetes and rare genetic diseases.