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

By Szabadkai G., Bianchi K., Várnai P., De Stefani D., Wieckowski M.R., Cavagna D., Nagy A.I., Balla T. and Rizzuto R.


The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca(2+), and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum Ca(2+)-release channel inositol 1,4,5-trisphosphate receptor (IP(3)R) 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 IP(3)R on the ER or mitochondrial surface, which directly enhanced Ca(2+) accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP(3)R and the mitochondrial Ca(2+) uptake machinery. Because organelle Ca(2+) homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis

Topics: Calcium, voltage-dependent anion channel, glucose-regulated protein 75, inositol 1, 4, 5-trisphosphate receptor
Year: 2007
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