Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels

TLDR

The voltage‑dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca²⁺, and cell‑death signaling between the endoplasmic reticulum and mitochondria, and because organelle Ca²⁺ homeostasis influences cellular functions and death signaling, the central location of grp75 may be a key control point of cell fate and pathogenesis. The study shows that VDAC1 is physically linked to the ER Ca²⁺‑release channel IP3R via the chaperone grp75. Recombinant expression of the IP3R ligand‑binding domain on the ER or mitochondrial surface enhanced mitochondrial Ca²⁺ accumulation, and grp75 knockdown abolished this effect, demonstrating chaperone‑mediated coupling of IP3R to mitochondrial Ca²⁺ uptake.

Abstract

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.