The study investigates the molecular mechanisms underlying the coupling of endoplasmic reticulum (ER) and mitochondrial Ca²⁺ channels. The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca²⁺, and cell death signaling between the ER and mitochondria. The authors demonstrate that VDAC1 is physically linked to the ER Ca²⁺-release channel, inositol 1,4,5-trisphosphate receptor (IP₃R), through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was confirmed by the recombinant expression of the IP₃R ligand-binding domain on the ER or mitochondrial surface, which enhanced Ca²⁺ accumulation in mitochondria. Knockdown of grp75 abolished this effect, highlighting chaperone-mediated conformational coupling between the IP₃R and the mitochondrial Ca²⁺ uptake machinery. The central role of grp75 in this interaction suggests it may represent an important control point for cell fate and pathogenesis.The study investigates the molecular mechanisms underlying the coupling of endoplasmic reticulum (ER) and mitochondrial Ca²⁺ channels. The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca²⁺, and cell death signaling between the ER and mitochondria. The authors demonstrate that VDAC1 is physically linked to the ER Ca²⁺-release channel, inositol 1,4,5-trisphosphate receptor (IP₃R), through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was confirmed by the recombinant expression of the IP₃R ligand-binding domain on the ER or mitochondrial surface, which enhanced Ca²⁺ accumulation in mitochondria. Knockdown of grp75 abolished this effect, highlighting chaperone-mediated conformational coupling between the IP₃R and the mitochondrial Ca²⁺ uptake machinery. The central role of grp75 in this interaction suggests it may represent an important control point for cell fate and pathogenesis.