The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca²⁺, and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum 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 shown by the recombinant expression of the ligand-binding domain of the IP₃R on the ER or mitochondrial surface, which directly enhanced Ca²⁺ accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP₃R and the mitochondrial Ca²⁺ uptake machinery. Because organelle Ca²⁺ homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis.