Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.
Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.
Hayashi
Teruo
T
Cellular Pathobiology Unit, Plasticity and Development Section, Cellular Neurobiology Research Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, MD 21224, USA. thayashi@intra.nida.nih.gov
Su
Tsung-Ping
TP
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D015854:Up-Regulation / Q000235:genetics; D000097605:Sigma-1 Receptor
D000255:Adenosine Triphosphate; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor