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. Mitochondria-associated membranes (MAMs) establish signaling microdomains for the exchange of Ca2+ and lipids between the endoplasmic reticulum (ER) and mitochondria.Ca2+ transfer between ER and mitochondria is critical for cellular physiology and functions, including mitochondrial metabolism and cell death.The presence, stability, levels, and activity of inositol 1,4,5-trisphosphate receptors, intracellular Ca2+-release channels, at the MAMs are tightly regulated by a plethora of mechanisms.Many proteins that are dysregulated or mutated in pathologies ranging from cancer to neurodegenerative disease reside at the MAMs, where they impact ER–mitochondrial Ca2+ transfer and affect cell function.Deranged ER–mitochondrial Ca2+ signaling drives pathogenesis and impacts disease outcomes.