The ER-mitochondria interface, where Ca²⁺ and cell death meet

Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca²⁺ flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IP₃Rs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca²⁺-transport system that delivers Ca²⁺ from the ER towards mitochondria. At the ER-mitochondria contact sites, the IP₃Rs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75). This IP₃R-GRP75-VDAC1 complex supports the efficient transfer of Ca²⁺ from the ER into the mitochondrial intermembrane space, from which the Ca²⁺ ions can reach the mitochondrial matrix through the mitochondrial calcium uniporter. Under physiological conditions, basal Ca²⁺ oscillations deliver Ca²⁺ to the mitochondrial matrix, thereby stimulating mitochondrial oxidative metabolism. However, when mitochondrial Ca²⁺ overload occurs, the increase in [Ca²⁺] will induce the opening of the mitochondrial permeability transition pore, thereby provoking cell death. The IP₃R-GRP75-VDAC1 complex forms a hub for several other proteins that stabilize the complex and/or regulate the complex's ability to channel Ca²⁺ into the mitochondria. These proteins and their mechanisms of action are discussed in the present review with special attention for their role in pathological conditions and potential implication for therapeutic strategies.