Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels.
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.
Szabadkai
György
G
Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, Emilia Romagna Laboratory for Genomics and Biotechnology, University of Ferrara, Ferrara 44100, Italy.
Bianchi
Katiuscia
K
Várnai
Péter
P
De Stefani
Diego
D
Wieckowski
Mariusz R
MR
Cavagna
Dario
D
Nagy
Anikó I
AI
Balla
Tamás
T
Rizzuto
Rosario
R
D000331:Aequorin; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D020798:Two-Hybrid System Techniques; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D018832:Molecular Chaperones; C494762:VDAC1 protein, human; C494764:Vdac1 protein, rat; C018551:glucose-regulated proteins; D000331:Aequorin; D015544:Inositol 1,4,5-Trisphosphate; D050995:Voltage-Dependent Anion Channel 1; D002118:Calcium